研究者データベース

小林 篤史(コバヤシ アツシ)
獣医学研究院 獣医学部門 臨床獣医科学分野
准教授

基本情報

所属

  • 獣医学研究院 獣医学部門 臨床獣医科学分野

職名

  • 准教授

学位

  • 博士(医学)(東北大学)

J-Global ID

研究キーワード

  • 神経病理学   クロイツフェルト・ヤコブ病   プリオン   

研究分野

  • ライフサイエンス / ウイルス学 / プリオン
  • ライフサイエンス / 実験病理学 / 神経病理学

職歴

  • 2014年10月 - 現在 北海道大学 大学院獣医学研究院比較病理学教室 准教授
  • 2013年04月 - 2014年10月 東北大学 大学院医学系研究科病態神経学分野 講師
  • 2006年04月 - 2013年03月 東北大学 大学院医学系研究科病態神経学分野 助教

学歴

  • 2002年04月 - 2006年03月   東北大学   大学院医学系研究科
  • 1996年04月 - 2002年03月   北海道大学   獣医学部

所属学協会

  • 日本獣医学会   日本神経病理学会   アジア太平洋プリオン研究会   日本神経感染症学会   

研究活動情報

論文

  • Ganbaatar O, Konnai S, Okagawa T, Nojima Y, Maekawa N, Minato E, Kobayashi A, Ando R, Sasaki N, Miyakoshi D, Ichii O, Kato Y, Suzuki Y, Murata S, Ohashi K
    PLOS One 15 11 e0234218  2020年11月 [査読有り][通常論文]
  • Lesa A. Thompson, Atsuya Morita, Shoko Murakami, Noboru Sasaki, Miou Murashita, Ryou Yamazaki, Atsushi Kobayashi, Takashi Kimura, Mitsuyoshi Takiguchi
    J Vet Diagn Invest 32 6 953 - 956 2020年11月 [査読有り][通常論文]
  • Erdemsurakh O, Purevdorj B, Ochirbat K, Adilbish A, Vanaabaatar B, Aoshima K, Kobayashi A, Kimura T
    Vet Pathol 57 6 807 - 811 2020年11月 [査読有り][通常論文]
  • Ochbayar Erdemsurakh, Khurtsbaatar Ochirbat, Ulziisaikhan Gombosuren, Batbold Tserendorj, Baatarjargal Purevdorj, Batbaatar Vanaabaatar, Keisuke Aoshima, Atsushi Kobayashi, Takashi Kimura
    The Journal of veterinary medical science 82 9 1247 - 1252 2020年09月24日 [査読有り][通常論文]
     
    Glanders is a contagious and fatal equine disease caused by the gram-negative bacterium Burkholderia mallei.B. mallei is prevalent among horse populations in Asia, the Middle East, and South America. More than four million horses have been registered in Mongolia in 2020. However, the resent prevalence of glanders has not been well investigated. In this study, we aimed to investigate the seropositivity of B. mallei in horse populations in Mongolia using the complement fixation test (CFT) and Rose Bengal plate agglutination test (RBT). We randomly collected blood samples from horses in central and eastern Mongolia between 2018 and 2019. Of 337 horses, 26 (7.7%) and 28 (8.3%) were seropositive using RBT and CFT, respectively. Interestingly, seropositivity in horses resulting from crossbreeding of Mongolian native horses with thoroughbred horses was higher than that in Mongolian native horses. Our observations suggest that equine glanders are still endemic to Mongolia.
  • Mika K Kaneko, Masato Sano, Junko Takei, Teizo Asano, Yusuke Sayama, Hideki Hosono, Atsushi Kobayashi, Satoru Konnai, Yukinari Kato
    Monoclonal antibodies in immunodiagnosis and immunotherapy 39 4 144 - 155 2020年08月21日 [査読有り][通常論文]
     
    Anti-podoplanin (PDPN) monoclonal antibodies (mAbs) are needed as markers for lymphatic endothelial cells or type I alveolar cells in immunohistochemical analyses. We have developed anti-PDPN mAbs for many species, including humans, mice, rats, rabbits, dogs, cats, bovines, pigs, Tasmanian devils, alpacas, tigers, whales, goats, horses, and bears. This study develops and characterizes anti-sheep PDPN (sPDPN) mAbs using Cell-Based Immunization and Screening (CBIS) method. A RAP14 tag was added to the N-terminus of sPDPN, and an anti-RAP14 tag mAb (PMab-2) was used to measure the expression level of sPDPN in flow cytometry and Western blots. We immunized mice with sPDPN-overexpressing Chinese hamster ovary (CHO)-K1 (CHO/sPDPN) cells and screened mAbs against sPDPN using flow cytometry. Two of the mAbs, PMab-253 (immunoglobulin M [IgM], kappa) and PMab-260 (IgM, kappa), detected CHO/sPDPN cells specifically using flow cytometry and Western blots. Both PMab-253 and PMab-260 stained the renal glomerulus and Bowman's capsule, lymphatic endothelial cells of the lung and colon, and type I alveolar cells of the lung, suggesting PMab-253 and PMab-260, which were developed by CBIS method, can be applied to functional analyses of sPDPN. We also determined the binding epitope of PMab-253 and PMab-260 using flow cytometry. Analysis of sPDPN deletion mutants revealed that the N-terminus of the PMab-253 and PMab-260 epitope exists between amino acids 110 and 115 of sPDPN. Analysis of sPDPN point mutations revealed that the critical epitope of PMab-253 and PMab-260 includes Thr112 and Ser113 of sPDPN, indicating that the PMab-253 and PMab-260 epitope are independent of the platelet aggregation-stimulating (PLAG) domain or the PLAG-like domain of sPDPN.
  • Hamaguchi T, Sakai K, Kobayashi A, Kitamoto T, Ae R, Nakamura Y, Sanjo N, Arai K, Koide M, Katada F, Harada M, Murai H, Murayama S, Tsukamoto T, Mizusawa H, Yamada M
    Emerg Infect Dis 26 6 1140 - 1146 2020年06月 [査読有り][通常論文]
  • Takeuchi H, Konnai S, Maekawa N, Minato E, Ichikawa Y, Kobayashi A, Okagawa T, Murata S, Ohashi K
    Front Vet Sci 7 330  2020年06月 [査読有り][通常論文]
  • Kobayashi A, Hirata T, Nishikaze T, Ninomiya A, Maki Y, Takada Y, Kitamoto T, Kinoshita T
    J Biol Chem 295 22 7789 - 7798 2020年05月29日 [査読有り][通常論文]
     
    Prion diseases are transmissible, lethal neurodegenerative disorders caused by accumulation of the aggregated scrapie form of the prion protein (PrPSc) after conversion of the cellular prion protein (PrPC). The glycosylphosphatidylinositol (GPI) anchor of PrPC is involved in prion disease pathogenesis, and especially sialic acid in a GPI side chain reportedly affects PrPC conversion. Thus, it is important to define the location and structure of the GPI anchor in human PrPC Moreover, the sialic acid linkage type in the GPI side chain has not been determined for any GPI-anchored protein. Here we report GPI glycan structures of human PrPC isolated from human brains and from brains of a knock-in mouse model in which the mouse prion protein (Prnp) gene was replaced with the human PRNP gene. LC-electrospray ionization-MS analysis of human PrPC from both biological sources indicated that Gly229 is the ω site in PrPC to which GPI is attached. Gly229 in human PrPC does not correspond to Ser231, the previously reported ω site of Syrian hamster PrPC We found that ∼41% and 28% of GPI anchors in human PrPCs from human and knock-in mouse brains, respectively, have N-acetylneuraminic acid in the side chain. Using a sialic acid linkage-specific alkylamidation method to discriminate α2,3 linkage from α2,6 linkage, we found that N-acetylneuraminic acid in PrPC's GPI side chain is linked to galactose through an α2,3 linkage. In summary, we report the GPI glycan structure of human PrPC, including the ω-site amino acid for GPI attachment and the sialic acid linkage type.
  • Shinya Goto, Satoru Konnai, Yuki Hirano, Junko Kohara, Tomohiro Okagawa, Naoya Maekawa, Yamato Sajiki, Kei Watari, Erina Minato, Atsuhi Kobayashi, Satoshi Gondaira, Hidetoshi Higuchi, Masateru Koiwa, Motoshi Tajima, Eiji Taguchi, Masaru Ishida, Ryoko Uemura, Shinji Yamada, Mika K. Kaneko, Yukinari Kato, Keiichi Yamamoto, Mikihiro Toda, Yasuhiko Suzuki, Shiro Murata, Kazuhiko Ohashi
    JAPANESE JOURNAL OF VETERINARY RESEARCH 68 2 77 - 90 2020年05月 [査読有り][通常論文]
     
    Mycoplasma bovis (M. bovis) is a highly contagious pathogen and M. bovis-associated diseases, particularly pneumonia, occur predominantly as herd enzootics, causing considerable economic losses because of calf mortality, weight loss in surviving calves. In our previous studies, the programmed death-1 (PD-1)/ PD-ligand 1 (PD-L1) pathway and prostaglandin E-2 (PGE(2)) were shown to be involved in the immunosuppression during chronic infectious diseases in cattle. In this study, the efficacy of dual blockade of the PD-1/PD-L1 pathway and PGE(2) in M. bovis infection in vivo was investigated using anti-bovine PDLl rat-bovine chimeric antibody, Boch4G12, and cyclooxygenase 2 (COX-2) inhibitor, meloxicam. The calves treated with Boch4G12 and meloxicam significantly enhanced M. bovis-specific IFN--gamma response after the administration. On the other hand, IFN-gamma response was not activated in the controls and cattle treated with meloxicam alone throughout the experimental period. Interestingly, bacterial loads in nasal discharge and bronchoalveolar lavage fluid among calves treated with Boch4G12 with or without meloxicam were significantly decreased. These results suggest that the combination of anti-PD-L1 antibody with a COX-2 inhibitor is a candidate for therapeutic applications in calves infected with M. bovis.
  • Atsushi Kobayashi
    Brain Nerve 72 4 437 - 443 2020年04月 [査読有り][招待有り]
  • Goto S, Konnai S, Hirano Y, Kohara J, Okagawa T, Maekawa N, Sajiki Y, Watari K, Minato E, Kobayashi A, Gondaira S, Higuchi H, Koiwa M, Tajima M, Taguchi E, Uemura R, Yamada S, Kaneko M, Kato Y, Yamamoto K, Toda M, Suzuki Y, Murata S, Ohashi K
    Front Vet Sci 7 12 - 12 2020年02月 [査読有り][通常論文]
     
    Bovine mycoplasmosis caused by Mycoplasma bovis results in pneumonia and mastitis in cattle. We previously demonstrated that the programmed death 1 (PD-1)/PD-ligand 1 (PD-L1) pathway is involved in immune dysfunction during M. bovis infection and that prostaglandin E2 (PGE2) suppressed immune responses and upregulated PD-L1 expression in Johne's disease, a bacterial infection in cattle. In this study, we investigated the role of PGE2 in immune dysfunction and the relationship between PGE2 and the PD-1/PD-L1 pathway in M. bovis infection. In vitro stimulation with M. bovis upregulated the expressions of PGE2 and PD-L1 presumably via Toll-like receptor 2 in bovine peripheral blood mononuclear cells (PBMCs). PGE2 levels of peripheral blood in infected cattle were significantly increased compared with those in uninfected cattle. Remarkably, plasma PGE2 levels were positively correlated with the proportions of PD-L1+ monocytes in M. bovis-infected cattle. Additionally, plasma PGE2 production in infected cattle was negatively correlated with M. bovis-specific interferon (IFN)-γ production from PBMCs. These results suggest that PGE2 could be one of the inducers of PD-L1 expression and could be involved in immunosuppression during M. bovis infection. In vitro blockade assays using anti-bovine PD-L1 antibody and a cyclooxygenase 2 inhibitor significantly upregulated the M. bovis-specific IFN-γ response. Our study findings might contribute to the development of novel therapeutic strategies for bovine mycoplasmosis that target PGE2 and the PD-1/PD-L1 pathway.
  • Minato E, Kobayashi A, Aoshima K, Fukushi H, Kimura T
    Microbiol Immunol 64 2 123 - 132 2020年02月 [査読有り][通常論文]
  • Yasushi Iwasaki, Keita Hiraga, Shota Ito, Tetsuo Ando, Akio Akagi, Yuichi Riku, Maya Mimuro, Hiroaki Miyahara, Atsushi Kobayashi, Tetsuyuki Kitamoto, Mari Yoshida
    Neuropathology : official journal of the Japanese Society of Neuropathology 39 6 452 - 460 2019年12月 [査読有り][通常論文]
     
    Comprehensive analysis is required for the accurate diagnosis of MV2-type sporadic Creutzfeldt-Jakob disease (sCJD) because it shows a wide clinicopathological spectrum. Here, we describe the clinical findings and neuropathologic observations of an autopsy-confirmed MV2K-type sCJD case with extensive spongiform changes of the cerebral cortex. In the early disease stages, the patient exhibited gait disturbance with ataxia and gradually showed cognitive dysfunction. Diffusion-weighted magnetic resonance images revealed hyperintense regions in the cerebral cortex, basal ganglia, and particularly in the thalamus. Prion protein (PrP) gene analysis revealed no mutations, and polymorphic codon 129 exhibited methionine and valine heterozygosity. During the course of the disease, a startle reaction was observed, whereas myoclonus was not observed. Electroencephalography showed no periodic sharp wave complexes. The patient died at age 61 years with 13 months total disease duration and did not reach the akinetic mutism state. Pathologic investigation revealed extensive fine vacuole-type spongiform change in the cerebral cortex, and the appearance of vacuolation tended to be more pronounced in the deeper layers. Numerous kuru plaques were observed in the cerebellum. PrP immunostaining revealed extensive diffuse synaptic-type PrP deposition in the cerebral cortex, and the finding was prominent in the deeper layer with perineuronal-type PrP deposition. In the limbic system, basal ganglia, and thalamus, mixed small plaque-type PrP with synaptic-type PrP deposition was observed. In the cerebellar cortex, diffuse synaptic-type PrP depositions were observed with numerous strongly immunopositive plaques. Western blot analysis of examined brain samples revealed mixed type 2 PrPSc (scrapie type) and intermediate-type PrPSc .
  • Morita A, Aoshima K, Onishi S, Shibata Y, Yasui H, Kobayashi A, Kimura T
    Res Vet Sci 127 1 - 10 2019年12月 [査読有り][通常論文]
  • Takeuchi A, Mohri S, Kai H, Tamaoka A, Kobayashi A, Mizusawa H, Iwasaki Y, Yoshida M, Shimizu H, Murayama S, Kuroda S, Morita M, Parchi P, Kitamoto T
    Brain Commun 1 1 fcz045  2019年12月 [査読有り][通常論文]
  • Kato Y, Takei J, Sayama Y, Sano M, Konnai S, Kobayashi A, Harada H, Yamada S, Kaneko MK
    Monoclon Antib Immunodiagn Immunother. 38 5 230 - 233 2019年10月 [査読有り][通常論文]
  • Yamato Sajiki, Satoru Konnai, Tomohiro Okagawa, Asami Nishimori, Naoya Maekawa, Shinya Goto, Kei Watari, Erina Minato, Atsushi Kobayashi, Junko Kohara, Shinji Yamada, Mika K Kaneko, Yukinari Kato, Hirofumi Takahashi, Nobuhiro Terasaki, Akira Takeda, Keiichi Yamamoto, Mikihiro Toda, Yasuhiko Suzuki, Shiro Murata, Kazuhiko Ohashi
    Journal of immunology (Baltimore, Md. : 1950) 203 5 1313 - 1324 2019年09月01日 [査読有り][通常論文]
     
    Bovine leukemia virus (BLV) infection is a chronic viral infection of cattle and endemic in many countries, including Japan. Our previous study demonstrated that PGE2, a product of cyclooxygenase (COX) 2, suppresses Th1 responses in cattle and contributes to the progression of Johne disease, a chronic bacterial infection in cattle. However, little information is available on the association of PGE2 with chronic viral infection. Thus, we analyzed the changes in plasma PGE2 concentration during BLV infection and its effects on proviral load, viral gene transcription, Th1 responses, and disease progression. Both COX2 expression by PBMCs and plasma PGE2 concentration were higher in the infected cattle compared with uninfected cattle, and plasma PGE2 concentration was positively correlated with the proviral load. BLV Ag exposure also directly enhanced PGE2 production by PBMCs. Transcription of BLV genes was activated via PGE2 receptors EP2 and EP4, further suggesting that PGE2 contributes to disease progression. In contrast, inhibition of PGE2 production using a COX-2 inhibitor activated BLV-specific Th1 responses in vitro, as evidenced by enhanced T cell proliferation and Th1 cytokine production, and reduced BLV proviral load in vivo. Combined treatment with the COX-2 inhibitor meloxicam and anti-programmed death-ligand 1 Ab significantly reduced the BLV proviral load, suggesting a potential as a novel control method against BLV infection. Further studies using a larger number of animals are required to support the efficacy of this treatment for clinical application.
  • Minato E, Aoshima K, Kobayashi A, Ohnishi N, Sasa N, Kimura T
    Vet Pathol 56 5 703 - 710 2019年09月 [査読有り][通常論文]
  • Takei J, Furusawa Y, Yamada S, Nakamura T, SayamaY, Sano M, Konnai S, Kobayashi A, Harada H, Kaneko MK, Kato Y
    Monoclon Antib Immunodiagn Immunother. 38 4 171 - 174 2019年06月 [査読有り][通常論文]
  • Shinji Yamada, Shunsuke Itai, Takuro Nakamura, Junko Takei, Masato Sano, Satoru Konnai, Atsushi Kobayashi, Shotaro Nakagun, Yoshiyasu Kobayashi, Mika K Kaneko, Yukinari Kato
    Monoclonal antibodies in immunodiagnosis and immunotherapy 38 3 104 - 107 2019年06月 [査読有り][通常論文]
     
    Podoplanin (PDPN)/T1 alpha is known as a specific marker of lymphatic endothelial cells and type I alveolar cells. Sensitive and specific monoclonal antibodies (mAbs) for PDPN are needed for immunohistochemical analyses. Recently, we developed an anticetacean PDPN mAb, PMab-237. Herein, immunohistochemical analyses showed that PMab-237 strongly detected pulmonary type I alveolar cells, renal podocytes, and lymphatic endothelial cells of the harbor porpoise. These findings suggest that PMab-237 may be useful for immunohistochemical analyses for cetacean tissues.
  • Kobayashi A, Iwasaki Y, Takao M, Saito Y, Iwaki T, Qi Z, Torimoto R, Shimazaki T, Munesue Y, Isoda N, Sawa H, Aoshima K, Kimura T, Kondo H, Mohri S, Kitamoto T
    Am J Pathol 189 6 1276 - 1283 2019年06月 [査読有り][通常論文]
  • Iwasaki Y, Kato H, Ando T, Akagi A, Mimuro M, Miyahara H, Kobayashi A, Kitamoto T, Yoshida M
    Neuropathology 39 3 240 - 247 2019年06月 [査読有り][通常論文]
  • Kobayashi A, Matsuura Y, Takeuchi A, Yamada M, Miyoshi I, Mohri S, Kitamoto T
    Brain Pathol 29 2 155 - 163 2019年03月 [査読有り][通常論文]
  • Kobayashi A, Qi Z, Shimazaki T, Munesue Y, Miyamoto T, Isoda N, Sawa H, Aoshima K, Kimura T, Mohri S, Kitamoto T, Yamashita T, Miyoshi I
    Am J Pathol 189 3 677 - 686 2019年03月 [査読有り][通常論文]
  • Kato Y, Yamada S, Itai S, Kobayashi A, Konnai S, Kaneko MK
    Monoclon Antib Immunodiagn Immunother. 37 6 272 - 274 2018年12月 [査読有り][通常論文]
  • Kato Y, Yamada S, Itai S, Konnai S, Kobayashi A, Kaneko MK
    Monoclon Antib Immunodiagn Immunother. 37 6 269 - 271 2018年12月 [査読有り][通常論文]
  • Kato Y, Yamada S, Itai S, Kobayashi A, Konnai S, Kaneko MK
    Monoclon Antib Immunodiagn Immunother. 37 6 265 - 268 2018年12月 [査読有り][通常論文]
  • Furukawa F, Sanjo N, Kobayashi A, Hamaguchi T, Yamada M, Kitamoto T, Mizusawa H, Yokota T
    Prion 12 5-6 315 - 319 2018年11月 [査読有り][通常論文]
  • Aoshima K, Fukui Y, Gulay KCM, Erdemsurakh O, Morita A, Kobayashi A, Kimura T
    BMC Vet Res 14 1 301  2018年10月 [査読有り][通常論文]
  • Ishizawa K, Mitsufuji T, Shioda K, Kobayashi A, Komori T, Nakazato Y, Kitamoto T, Araki N, Yamamoto T, Sasaki A
    Brain Behav 8 10 e01117  2018年10月 [査読有り][通常論文]
  • Tomoya Morita, Kensuke Nakamura, Tatsuyuki Osuga, Atsushi Kobayashi, Osamu Ichii, Akira Yabuki, Mitsuyoshi Takiguchi
    The Journal of veterinary medical science 80 6 939 - 944 2018年06月29日 [査読有り][通常論文]
     
    A 12 year-old intact male Pembroke Welsh corgi weighing 10.8 kg was presented for evaluation of a 3-month history of dyspnea, and a 1-week history of exercise intolerance and anorexia. Severe hypoxemia (PaO2 56 mmHg), diffuse lung alveolar infiltration, and severe pulmonary hypertension (PH) (tricuspid regurgitation pressure gradient was 81 mmHg) were identified. A tentative diagnosis of severe PH due to lung disease or pulmonary thromboembolism was made and treated intensively. After 5 days of hospitalization, the dog died despite oxygen supplementation and anticoagulant therapy. This dog was diagnosed as unclassified interstitial lung disease based on histopathological findings.
  • Sayed Samim Rahpaya, Shinobu Tsuchiaka, Mai Kishimoto, Mami Oba, Yukie Katayama, Yuka Nunomura, Saki Kokawa, Takashi Kimura, Atsushi Kobayashi, Yumi Kirino, Tamaki Okabayashi, Nariaki Nonaka, Hirohisa Mekata, Hiroshi Aoki, Mai Shiokawa, Moeko Umetsu, Tatsushi Morita, Ayako Hasebe, Keiko Otsu, Tetsuo Asai, Tomohiro Yamaguchi, Shinji Makino, Yoshiteru Murata, Ahmad Jan Abi, Tsutomu Omatsu, Tetsuya Mizutani
    Journal of veterinary science 19 3 350 - 357 2018年05月31日 [査読有り][通常論文]
     
    Bovine abortion, diarrhea, and respiratory disease complexes, caused by infectious agents, result in high and significant economic losses for the cattle industry. These pathogens are likely transmitted by various vectors and reservoirs including insects, birds, and rodents. However, experimental data supporting this possibility are scarce. We collected 117 samples and screened them for 44 bovine abortive, diarrheal, and respiratory disease complex pathogens by using Dembo polymerase chain reaction (PCR), which is based on TaqMan real-time PCR. Fifty-seven samples were positive for at least one pathogen, including bovine viral diarrhea virus, bovine enterovirus, Salmonella enterica ser. Dublin, Salmonella enterica ser. Typhimurium, and Neospora caninum; some samples were positive for multiple pathogens. Bovine viral diarrhea virus and bovine enterovirus were the most frequently detected pathogens, especially in flies, suggesting an important role of flies in the transmission of these viruses. Additionally, we detected the N. caninum genome from a cockroach sample for the first time. Our data suggest that insects (particularly flies), birds, and rodents are potential vectors and reservoirs of abortion, diarrhea, and respiratory infectious agents, and that they may transmit more than one pathogen at the same time.
  • Yoshinori Shimamoto, Junko Nio-Kobayashi, Hiroshi Watarai, Masashi Nagano, Natsuko Saito, Eiki Takahashi, Hidetoshi Higuchi, Atsushi Kobayashi, Takashi Kimura, Hiroshi Kitamura
    Veterinary immunology and immunopathology 198 6 - 13 2018年04月 [査読有り][通常論文]
     
    The scavenger receptor CD163 is widely used as a cell signature for alternatively active "M2" macrophages in mammals. In this study, we generated two monoclonal antibodies, ABM-1A9 and ABM-2D6, against the extracellular region of bovine CD163. Conventional Western blotting using the antibodies yielded immunoreactive bands of bovine CD163 at 130 and 150 kDa in non-reduced and reduced spleen lysates, respectively. The minimum limit of detectable concentration of both antibodies was relatively lower (5.0 ng/mL) than that of the anti-human CD163 monoclonal antibody AM-3 K (>1.0 μg/mL), which has been used previously for the detection of bovine CD163. An immunohistochemical study using formalin-fixed paraffin-embedded sections revealed that ABM-1A9 and ABM-2D6 clearly stained some Iba1+ macrophages in the lymph nodes of cattle with mastitis. Moreover, the CD163-stained macrophages were frequently observed engulfing leukocytes. ELISA using ABM-2D6 distinguished levels of circulating soluble CD163 in healthy cattle (less than 16.9 pmol/mL) and cattle with mastitis (more than 33.7 pmol/mL). These new monoclonal antibodies can be used in the diagnosis and evaluation of inflammatory disease prognosis in cattle with immunohistological analyses and blood test applications.
  • Yoshiko Munesue, Taishi Shimazaki, Zechen Qi, Norikazu Isoda, Hirofumi Sawa, Keisuke Aoshima, Takashi Kimura, Shirou Mohri, Tetsuyuki Kitamoto, Atsushi Kobayashi
    Neuroscience Letters 668 43 - 47 2018年03月06日 [査読有り][通常論文]
     
    Evaluation of transmission properties is important for the differential diagnosis of a subgroup of acquired Creutzfeldt-Jakob disease (CJD) with methionine homozygosity at polymorphic codon 129 of the PRNP gene, an intermediate type abnormal prion protein (PrP), and kuru plaques, denoted as acquired CJD-MMiK. The present study aimed to develop a quick evaluation system of the transmission properties of acquired CJD-MMiK. In the PrP-humanized mice intraperitoneally inoculated with brain homogenates from an acquired CJD-MMiK patient, accumulation of abnormal PrP was observed in follicular dendritic cells of the spleen at 75 days post-inoculation. The transmission properties of acquired CJD-MMiK were quite different from those of sporadic CJD with the same PRNP codon 129 genotype. Moreover, even at 14 days post-inoculation, the characteristic transmission properties of acquired CJD-MMiK could be detected. These findings suggest that the bioassay using follicular dendritic cells of the spleen, named as a FDC assay, can be an easy, time-saving, and useful method to distinguish acquired CJD-MMiK from sporadic CJD.
  • Yoko Ito, Nobuo Sanjo, Masaki Hizume, Atsushi Kobayashi, Tetsuya Ohgami, Katsuya Satoh, Tsuyoshi Hamaguchi, Masahito Yamada, Tetsuyuki Kitamoto, Hidehiro Mizusawa, Takanori Yokota
    Biochemical and Biophysical Research Communications 496 4 1055 - 1061 2018年02月19日 [査読有り][通常論文]
     
    Valine-to-isoleucine substitution at codon 180 of the prion protein gene is only observed in patients with Creutzfeldt-Jakob disease and accounts for approximately half of all cases of genetic prion disease in Japan. In the present study, we investigated the biochemical characteristics of valine-to-isoleucine substitution at codon 180 in the prion protein gene, using samples obtained from the autopsied brains of seven patients with genetic Creutzfeldt-Jakob disease exhibiting this mutation (diagnoses confirmed via neuropathological examination). Among these patients, we observed an absence of diglycosylated and monoglycosylated forms of PrPres at codon 181. Our findings further indicated that the abnormal prion proteins were composed of at least three components, although smaller carboxyl-terminal fragments were predominant. Western blot analyses revealed large amounts of PrPres in the cerebral neocortices, where neuropathological examination revealed marked spongiosis. Relatively smaller amounts of PrPres were detected in the hippocampus, where milder spongiosis was observed, than in the cerebral neocortex. These findings indicate that abnormal prion proteins in the neocortex are associated with severe toxicity, resulting in severe spongiosis. Our findings further indicate that the valine-to-isoleucine substitution is not a polymorphism, but rather an authentic pathogenic mutation associated with specific biochemical characteristics that differ from those observed in sporadic Creutzfeldt-Jakob disease.
  • Aprilia Maharani, Keisuke Aoshima, Shinichi Onishi, Kevin Christian Montecillo Gulay, Atsushi Kobayashi, Takashi Kimura
    Journal of Veterinary Medical Science 80 2 213 - 218 2018年02月01日 [査読有り][通常論文]
     
    Canine hemangiosarcoma (HSA) is one of the most common mesenchymal tumors in dogs. Its high metastatic and growth rates are usually associated with poor prognosis. Neoplastic cells of HSA can show various levels of cellular atypia in the same mass and may consist of various populations at different differentiated stages. Up to present, however, there is no report analyzing their differentiation states by comparing cellular atypia with differentiation-related protein expressions. To evaluate whether cellular atypia can be used as a differentiation marker in HSA, we analyzed correlation between cellular atypia and intensities of CD31 and von Willebrand Factor (vWF) staining in HSA cases. We also compared cellular atypia and expression levels of CD31 and vWF in each growth patterns. Our results show that cellular atypia was negatively correlated to CD31 and vWF expression levels but no significant correlation was found between growth patterns and cellular atypia or CD31 and vWF expression levels. Our study suggests that cellular atypia is useful for identifying differentiation levels in HSA cases. This study also provides useful information to determine differentiation levels of cell populations within HSA based only on morphological analysis, which will aid further HSA research such as identifying undifferentiation markers of endothelial cells or finding undifferentiated cell population in tissue sections.
  • Atsushi Kobayashi, Tetsuyuki Kitamoto, Hidehiro Mizusawa
    Handbook of Clinical Neurology 153 207 - 218 2018年01月01日 [査読有り][通常論文]
     
    Iatrogenic transmission of Creutzfeldt–Jakob disease (CJD) has occurred through particular medical procedures. Among them, dura mater grafts and pituitary-derived growth hormone obtained from human cadavers undiagnosed as CJD are the most frequent sources of infection. Recent advances in our knowledge about dura mater graft- and human pituitary-derived growth hormone-associated CJD patients have revealed that the combination of the infected CJD strain and the PRNP genotype of the patient determines their clinical, neuropathologic, and biochemical features. In this chapter, we summarize the clinical, neuropathologic, biochemical, and diagnostic features of dura mater graft- and human pituitary-derived growth hormone-associated CJD patients for the appropriate diagnosis of iatrogenic CJD.
  • Iwasaki Y, Saito Y, Aiba I, Kobayashi A, Mimuro M, Kitamoto T, Yoshida M
    NEUROPATHOLOGY 37 3 241 - 248 2017年06月 [査読有り][通常論文]
     
    MV2-type sporadic Creutzfeldt-Jakob disease (sCJD), which was previously called "Kuru-plaque variant", was gradually revealed to have a wide spectrum and has been classified into three pathological subtypes: MV2K, MV2C and MV2K + C. We herein describe the detailed clinical findings and neuropathologic observations from an autopsied MV2K + C-type Japanese sCJD case with widespread cerebral cortical pathology and Kuru plaques. In the early stages of the disease, the patient exhibited gait disturbance with ataxia and dysarthria as well as gradual appearance of cognitive dysfunction. Diffusion-weighted images (DWI) on MRI revealed extensive cerebral cortical hyperintensity. Pathologic investigation revealed extensive spongiform change in the cerebral cortex, particularly in the deeper layers. Vacuole size varied, and some were confluent. Prion protein (PrP) immunostaining revealed extensive PrP deposition in the cerebral cortex, basal ganglia, thalamus, cerebellum, brainstem and spinal cord. In the cerebral cortex, synaptic-type, Kuru plaque-like, and coarse plaque-type PrP depositions were mainly observed, along with some perivacuolar-type PrP depositions. Kuru plaques and coarse plaque-type PrP depositions also were observed in the cerebellar cortex. PrP gene analysis revealed no mutations, and polymorphic codon 129 exhibited Met/Val heterozygosity. Western blot analysis revealed a mixture of intermediate-type PrPSc and type 2 PrPSc. Based on previous reports regarding MV2-type sCJD and the clinicopathologic findings of the present case, we speculated that it may be possible to clinically distinguish each MV2 subtype. Clinical presentation of the MV2K + C subtype includes predominant cerebral cortical involvement signs with ataxia and DWI hyperintensity of the cerebral cortex on MRI.
  • Application of protein misfolding cyclic amplification for the rapid diagnosis of acquired Creutzfeldt-Jakob disease
    Takeuchi A, Kobayashi A, Morita M, Kitamoto T
    Med Res Arch 5 4 2017年04月 [査読有り][通常論文]
  • Sehgal A, Kobayashi A, Donaldson DS, Mabbott NA
    IMMUNOBIOLOGY 222 2 316 - 326 2017年02月 [査読有り][通常論文]
     
    M cells reside within the follicle-associated epithelium (FAE) overlying the gut-associated lymphoid tissues. These unique phagocytic epithelial cells enable the mucosal immune system to sample antigens within the lumen of the intestine. The differentiation of M cells from uncommitted precursors in the FAE is dependent on the production of receptor activator of nuclear factor-KB ligand (RANKL) by subepithelial stromal cells. The ligation of a variety of cell surface receptors activates the nuclear factor-kappa B (NF-kappa B) family of transcription factors which in-turn induce the transcription of multiple target genes. RANKL-stimulation can stimulate the nuclear translocation of the NF-kappa B subunit c-Rel. We therefore used cRel-deficient mice to determine whether the differentiation and functional maturation of M cells in the Peyer's patches was dependent on c-Rel. Our data show that c-Rel-deficiency does not influence the expression of RANKL or RANK in Peyer's patches, or the induction of M-cell differentiation in the FAE. RANKL-stimulation in the differentiating M cells induces the expression of SpiB which is essential for their subsequent maturation. However, SpiB expression in the FAE was also unaffected in the absence of c-Rel. As a consequence, the functional maturation of M cells was not impaired in the Peyer's patches of c-Rel-deficient mice. Although our data showed that the specific expression of CCL20 and ubiquitin D in the FAE was not impeded in the absence of c-Rel, the expression of ubiquitin D was dramatically reduced in the B cell-follicles of c-Rel-deficient mice. Coincident with this, we also observed that the status of follicular dendritic cells in the B cell-follicles was dramatically reduced in Peyer's patches from c-Rel-deficient mice. Taken together, our data show that c-Rel is dispensable for the RANKL-mediated differentiation and functional maturation of M cells. (C) 2016 The Authors. Published by Elsevier GmbH.
  • Mikihiro Yamazaki, Takahiro Fukuda, Atsushi Kobayashi, Hideki Takubo
    Brain and Nerve 68 10 1229 - 1238 2016年10月01日 [査読有り][招待有り]
  • Atsushi Kobayashi, Piero Parchi, Masahito Yamada, Shirou Mohri, Tetsuyuki Kitamoto
    NEUROPATHOLOGY 36 3 305 - 310 2016年06月 [査読有り][招待有り]
     
    As an experimental model of acquired Creutzfeldt-Jakob disease (CJD), we performed transmission studies of sporadic CJD using knock-in mice expressing human prion protein (PrP). In this model, the inoculation of the sporadic CJD strain V2 into animals homozygous for methionine at polymorphic codon 129 (129M/M) of the PRNP gene produced quite distinctive neuropathological and biochemical features, that is, widespread kuru plaques and intermediate type abnormal PrP (PrPSc). Interestingly, this distinctive combination of molecular and pathological features has been, to date, observed in acquired CJD but not in sporadic CJD. Assuming that these distinctive phenotypic traits are specific for acquired CJD, we revisited the literature and found two cases showing widespread kuru plaques despite the 129M/M genotype, in a neurosurgeon and in a patient with a medical history of neurosurgery without dura mater grafting. By Western blot analysis of brain homogenates, we revealed the intermediate type of PrPSc in both cases. Furthermore, transmission properties of brain extracts from these two cases were indistinguishable from those of a subgroup of dura mater graft-associated iatrogenic CJD caused by infection with the sporadic CJD strain V2. These data strongly suggest that the two atypical CJD cases, previously thought to represent sporadic CJD, very likely acquired the disease through exposure to prion-contaminated brain tissues. Thus, we propose that the distinctive combination of 129M/M genotype, kuru plaques, and intermediate type PrPSc, represents a reliable criterion for the identification of acquired CJD cases among presumed sporadic cases.
  • Atsuko Takeuchi, Atsushi Kobayashi, Piero Parchi, Masahito Yamada, Masanori Morita, Shusei Uno, Tetsuyuki Kitamoto
    LABORATORY INVESTIGATION 96 5 581 - 587 2016年05月 [査読有り][通常論文]
     
    There are two distinct subtypes of dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with methionine homozygosity at codon 129 of the PRNP gene. The majority of cases is represented by a non-plaque-type (np-dCJD) resembling sporadic CJD (sCJD)-MM1 or -MV1, while the minority by a plaque-type (p-dCJD). p-dCJD shows distinctive phenotypic features, namely numerous kuru plaques and an abnormal isoform of prion protein (PrPsc) intermediate in size between types 1 and 2. Transmission studies have shown that the unusual phenotypic features of p-dCJD are linked to the V2 prion strain that is associated with sCJD subtypes W2 or -MV2. In this study, we applied protein misfolding cyclic amplification (PMCA) using recombinant human prion protein as a substrate and demonstrated that p-dCJD prions show amplification features that are distinct from those of np-dCJD. Although no amplification of np-dCJD prions was observed with either 129 M or 129 V substrate, p-dCJD prions were drastically amplified with the 129 V substrates, despite the PRNP codon 129 incompatibility between seed and substrate. Moreover, by using a type 2 PrPsc-specific antibody not recognizing PrPsc in p-dCJD, we found that type 2 products are generated de novo from p-dCJD prions during PMCA with the 129 V substrates. These findings suggest that our cell-PMCA is a useful tool for easily and rapidly identifying acquired CJD associated with the transmission of the V2 CJD strain to codon 129 methionine homozygotes, based on the preference for the 129 V substrate and the type of the amplified products.
  • Atsushi Kobayashi, Yuichi Matsuura, Toru Iwaki, Yasushi Iwasaki, Mari Yoshida, Hitoshi Takahashi, Shigeo Murayama, Masaki Takao, Shinsuke Kato, Masahito Yamada, Shirou Mohri, Tetsuyuki Kitamoto
    BRAIN PATHOLOGY 26 1 95 - 101 2016年01月 [査読有り][通常論文]
     
    The genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene and the type (1 or 2) of abnormal prion protein in the brain are the major determinants of the clinicopathological features of sporadic Creutzfeldt-Jakob disease (CJD), thus providing molecular basis for classification of sporadic CJD, that is, MM1, MM2, MV1, MV2, VV1 or VV2. In addition to these pure cases, mixed cases presenting mixed neuropathological and biochemical features have also been recognized. The most frequently observed mixed form is the co-occurrence of MM1 and MM2, namely MM1+2. However, it has remained elusive whether MM1+2 could be a causative origin of dura mater graft-associated CJD (dCJD), one of the largest subgroups of iatrogenic CJD. To test this possibility, we performed transmission experiments of MM1+2 prions and a systematic neuropathological examination of dCJD patients in the present study. The transmission properties of the MM1+2 prions were identical to those of MM1 prions because MM2 prions lacked transmissibility. In addition, the neuropathological characteristics of MM2 were totally absent in dCJD patients examined. These results suggest that MM1+2 can be a causative origin of dCJD and causes neuropathological phenotype similar to that of MM1.
  • Atsushi Kobayashi, Kenta Teruya, Yuichi Matsuura, Tsuyoshi Shirai, Yoshikazu Nakamura, Masahito Yamada, Hidehiro Mizusawa, Shirou Mohri, Tetsuyuki Kitamoto
    ACTA NEUROPATHOLOGICA 130 2 159 - 170 2015年08月 [査読有り][通常論文]
     
    Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Straussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility.
  • Atsushi Kobayashi, Piero Parchi, Masahito Yamada, Paul Brown, Daniela Saverioni, Yuichi Matsuura, Atsuko Takeuchi, Shirou Mohri, Tetsuyuki Kitamoto
    JOURNAL OF VIROLOGY 89 7 3939 - 3946 2015年04月 [査読有り][通常論文]
     
    The genotype at polymorphic codon 129 of the PRNP gene has a profound influence on both phenotypic expression and prion strain susceptibility in humans. For example, while the most common sporadic Creutzfeldt-Jakob disease (CJD) subtype, sporadic CJD-MM1 (M1 strain), induces a single phenotype after experimental transmission regardless of the codon 129 genotype of the recipient animal, the phenotype elicited by sporadic CJD-VV2 (V2 strain), the second most common subtype, varies according to the host codon 129 genotype. In particular, the propagation of the V2 strain in codon 129 methionine homozygotes has been linked only to acquired forms of CJD such as plaque-type dura mater graft-associated CJD (dCJD), a subgroup of iatrogenic CJD with distinctive phenotypic features, but has never been observed in sporadic CJD cases. In the present report, we describe atypical CJD cases carrying codon 129 methionine homozygosity, in a neurosurgeon and in a patient with a medical history of neurosurgery without dural grafting, showing the distinctive phenotypic features and transmission properties of plaque-type dCJD. These findings raise the possibility that the two cases, previously thought to represent sporadic CJD, might actually represent acquired CJD caused by infection with the V2 strain. Thus, careful analyses of phenotypic features and transmission properties in atypical cases may be useful to distinguish acquired from sporadic cases of CJD. IMPORTANCE Susceptibility to and phenotypic expression of Creutzfeldt-Jakob disease (CJD) depend on both the prion strain and genotype at polymorphic codon 129 of the PRNP gene. For example, propagation of the second most common sporadic CJD strain (V2 strain) into codon 129 methionine homozygotes has been linked to plaque-type dura mater graft-associated CJD (dCJD), a subgroup of iatrogenic CJD with distinctive phenotypic features, but has never been observed in sporadic CJD. In the present report, we describe atypical CJD cases in a neurosurgeon and in a patient with a medical history of neurosurgery without dural grafting, showing the distinctive phenotypic features and transmission properties of plaque-type dCJD. These findings raise the possibility that the two cases, previously considered to represent sporadic CJD, might actually represent acquired CJD caused by infection with the V2 strain.
  • Neil A. Mabbott, Atsushi Kobayashi, Anuj Sehgal, Barry M. Bradford, Mari Pattison, David S. Donaldson
    BIOGERONTOLOGY 16 2 133 - 145 2015年04月 [査読有り][通常論文]
     
    Bacterial and viral infections of the gastrointestinal tract are more common in the elderly and represent a major cause of morbidity and mortality. The mucosal immune system provides the first line of defence against pathogens acquired by ingestion and inhalation, but its function is adversely affected in the elderly. This aging-related decline in the immune function is termed immunosenescence and is associated with diminished abilities to generate protective immunity, reduced vaccine efficacy, increased incidence of cancer, inflammation and autoimmunity, and the impaired ability to generate tolerance to harmless antigens. In this review we describe our current understanding of the effects immunosenescence has on the innate and adaptive arms of the mucosal immune system in the intestine. Current estimates suggest that by the year 2050 up to 40 % of the UK population will be over 65 years old, bringing with it important health challenges. A thorough understanding of the mechanisms that contribute to the development of immunosenescence is therefore crucial to help identify novel approaches to improve mucosal immunity in the elderly.
  • Kunihiko Araki, Yuta Nakano, Atsushi Kobayashi, Takashi Matsudaira, Akira Sugiura, Masaki Takao, Tetsuyuki Kitamoto, Shigeo Murayama, Tomokazu Obi
    NEUROPATHOLOGY 34 6 541 - 546 2014年12月 [査読有り][通常論文]
     
    We report a clinical case report of the MV2K+C subtype of sporadic Creutzfeldt-Jakob disease (sCJD). The patient was a 72-year-old woman who exhibited progressive dementia over the course of 22 months. Diffusion-weighted MRI during this period showed abnormal hyperintensity in the cerebral cortex in the early stage. The clinical course was similar to that of previously reported patients with the MV2K or MV2K+C subtype of sCJD. However, histopathological examination revealed unique features: severe extensive spongiform changes with perivacuolar deposits in the cerebrum and basal ganglia, plaque-like PrP deposits in the cerebrum, and only mild changes in the cerebellum with small amyloid plaques (approximate to 20m in diameter), smaller than those in the MV2K subtype or variant CJD (40-50m in diameter). Molecular analysis showed a methionine/valine heterozygosity at codon 129 and no pathogenic mutation in the PrP gene (PRNP). Western blot analysis of the protease-resistant PrP (PrPSc) in the right temporal pole revealed the type 2 pattern, which is characterized by a single unglycosylated band, in contrast to the doublet described for the typical MV2 subtype of sCJD. The other intermediate band might exist in the cerebellum with kuru plaques. Therefore, small amyloid plaques in the cerebellum can be crucial for MV2K+C subtype.
  • Tsuyoshi Shirai, Mihoko Saito, Atsushi Kobayashi, Masahiro Asano, Masaki Hizume, Shino Ikeda, Kenta Teruya, Masanori Morita, Tetsuyuki Kitamoto
    STRUCTURE 22 4 560 - 571 2014年04月 [査読有り][通常論文]
     
    The structural details of the essential entity of prion disease, fibril prion protein (PrPSc), are still elusive despite the large body of evidence supporting the prion hypothesis. Five major working models of PrPSc structure, which are not compatible with each other, have been proposed. However, no systematic evaluation has been performed on those models. We devised a method that combined systematic point mutation with threading on knowledge-based amino acid potentials. A comprehensive mutation experiment was performed on mouse prion protein, and the PrPSc conversion efficiency of each mutant was examined. The models were evaluated based on the mutation data by using the threading method. Although the data turned out to be rather more consistent with the models that assumed a conversion of the N-terminal region of core PrP into a beta helix than with others, substantial modifications were also required to further improve the current model based on recent experimental results.
  • Atsushi Kobayashi, Yuichi Matsuura, Shirou Mohri, Tetsuyuki Kitamoto
    ACTA NEUROPATHOLOGICA COMMUNICATIONS 2 32  2014年 [査読有り][通常論文]
     
    Dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) can be divided into two subgroups that exhibit distinct clinical and neuropathological features, with the majority represented by a non-plaque-type of dCJD (np-dCJD) and the minority by a plaque-type of dCJD (p-dCJD). The two distinct phenotypes of dCJD had been considered to be unrelated to the genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene or type (type 1 or type 2) of abnormal isoform of prion protein (PrPSc) in the brain, while these are major determinants of clinicopathological phenotypes of sporadic CJD (sCJD). The reason for the existence of two distinct subgroups in dCJD had remained elusive. Recent progress in research of the pathogenesis of dCJD has revealed that two distinct subgroups of dCJD are caused by infection with different PrPSc strains from sCJD, i. e., np-dCJD caused by infection with sCJD-MM1/MV1, and p-dCJD caused by infection with sCJD-VV2 or -MV2. These studies have also revealed previously unrecognized problems as follows: (i) the numbers of p-dCJD patients may increase in the future, (ii) the potential risks of secondary infection from dCJD, particularly from p-dCJD, may be considerable, and (iii) the effectiveness of the current PrPSc decontamination procedures against the PrPSc from p-dCJD is uncertain. To prevent secondary infection from p-dCJD, the establishment of effective decontamination procedures is an urgent issue. In this review, we summarize the past and future problems surrounding dCJD.
  • Temu Qina, Nobuo Sanjo, Masaki Hizume, Maya Higuma, Makoto Tomita, Ryuichiro Atarashi, Katsuya Satoh, Ichiro Nozaki, Tsuyoshi Hamaguchi, Yosikazu Nakamura, Atsushi Kobayashi, Tetsuyuki Kitamoto, Shigeo Murayama, Hiroyuki Murai, Masahito Yamada, Hidehiro Mizusawa
    BMJ OPEN 4 5 e004968  2014年 [査読有り][通常論文]
     
    Objectives: Genetic Creutzfeldt-Jakob disease (CJD) due to V180I mutation in the prion protein gene (PRNP) is of great interest because of the differences from sporadic CJD and other genetic prion diseases in terms of clinical features, as well as pathological and biochemical findings. However, few systematic observations about the clinical features in patients with this unique mutation have been published. Therefore, the goal of this study was to relate this mutation to other forms of CJD from a clinical perspective. Design: We analysed clinical symptoms, prion protein genetics, biomarkers in cerebrospinal fluid (CSF) and MRI of patients. Participants: 186 Japanese patients with the V180I mutation in PRNP. Results: Our results indicate that the V180I mutation caused CJD at an older age, with a slower progression and a lower possibility of developing myoclonus, cerebellar, pyramidal signs and visual disturbance compared with classical sporadic CJD with methionine homozygosity at codon 129 of PRNP. Cognitive impairment was the major symptom. Diffuse hyperintensity of the cerebral cortex in diffusion-weighted MRI might be helpful for diagnosis. Owing to the low positivity of PrPSc in the CSF, genetic analysis was often required for a differential diagnosis from slowly progressive dementia. Conclusions: We conclude that the V180I mutation in PRNP produces a late-developing and slow-developing, less severe form of CJD, whose lesions are uniquely distributed compared with sporadic and other genetic forms of CJD.
  • A. Kobayashi, D. S. Donaldson, C. Erridge, T. Kanaya, I. R. Williams, H. Ohno, A. Mahajan, N. A. Mabbott
    MUCOSAL IMMUNOLOGY 6 5 1027 - 1037 2013年09月 [査読有り][通常論文]
     
    The transcytosis of antigens across the follicle-associated epithelium (FAE) of Peyer's patches by microfold cells (M cells) is important for the induction of efficient immune responses to mucosal antigens. The mucosal immune response is compromised by ageing, but effects on M cells were unknown. We show that M-cell density in the FAE of aged mice was dramatically reduced. As a consequence, aged Peyer's patches were significantly deficient in their ability to transcytose particulate lumenal antigen across the FAE. Ageing specifically impaired the expression of Spi-B and the downstream functional maturation of M cells. Ageing also dramatically impaired C-C motif chemokine ligand 20 expression by the FAE. As a consequence, fewer B cells were attracted towards the FAE, potentially reducing their ability to promote M-cell maturation. Our study demonstrates that ageing dramatically impedes the functional maturation of M cells, revealing an important ageing-related defect in the mucosal immune system's ability to sample lumenal antigens.
  • Atsuko Takeuchi, Atsushi Kobayashi, James W. Ironside, Shirou Mohri, Tetsuyuki Kitamoto
    JOURNAL OF BIOLOGICAL CHEMISTRY 288 30 21659 - 21666 2013年07月 [査読有り][通常論文]
     
    To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease-resistant abnormal PrP in the brain and transmissibility of these humanized mouse-passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype.
  • Atsushi Kobayashi, Yasushi Iwasaki, Hiroyuki Otsuka, Masahito Yamada, Mari Yoshida, Yuichi Matsuura, Shirou Mohri, Tetsuyuki Kitamoto
    ACTA NEUROPATHOLOGICA COMMUNICATIONS 1 74  2013年 [査読有り][通常論文]
     
    Background: Sporadic Creutzfeldt-Jakob disease is classified according to the genotype at polymorphic codon 129 (M or V) of the prion protein (PrP) gene and the type (1 or 2) of abnormal isoform of PrP (PrPSc) in the brain. The most complicated entity in the current classification system is MV2, since it shows wide phenotypic variations, i.e., MV2 cortical form (MV2C), MV2 with kuru plaques (MV2K), or a mixed form (MV2K + C). To resolve their complicated pathogenesis, we performed a comprehensive analysis of the three MV2 subgroups based on histopathological, molecular, and transmission properties. Results: In histopathological and molecular analyses, MV2C showed close similarity to MM2 cortical form (MM2C) and could be easily discriminated from the other MV2 subgroups. By contrast, MV2K and MV2K + C showed the same molecular type and the same transmission type, and the sole difference between MV2K and MV2K + C was the presence of cortical pathology characteristic of MV2C/ MM2C. The remarkable molecular feature of MV2K or MV2K + C was a mixture of type 2 PrPSc and intermediate type PrPSc, which shows intermediate electrophoretic mobility between types 1 and 2 PrPSc. Modeling experiments using PrP-humanized mice indicated that MV2K contains a mixture of intermediate type PrPSc with the 129M genotype (Mi PrPSc) and type 2 PrPSc with the 129V genotype (V2 PrPSc) that originated from V2 PrPSc, whereas MV2C + K may also contain type 2 PrPSc with the 129M genotype and cortical pathology (M2C PrPSc) that lacks infectivity to the PrP-humanized mice in addition to Mi and V2 PrPSc. Conclusions: Taken together, the present study suggests that the phenotypic heterogeneity of MV2 stems from their different PrPSc origin(s).
  • Atsushi Kobayashi, David S Donaldson, Takashi Kanaya, Shinji Fukuda, J Kenneth Baillie, Tom C Freeman, Hiroshi Ohno, Ifor R Williams, Neil A Mabbott
    DNA research : an international journal for rapid publication of reports on genes and genomes 19 5 407 - 22 2012年10月 [査読有り][通常論文]
     
    The follicle-associated epithelium (FAE) overlying the Peyer's patches and the microfold cells (M cells) within it are important sites of antigen transcytosis across the intestinal epithelium. Using a meta-analysis approach, we identified a transcriptional signature that distinguished the FAE from a large collection of mouse cells and tissues. A co-expressed cluster of 21 FAE-specific genes was identified, and the analysis of the transcription factor binding site motifs in their promoter regions indicated that these genes shared an underlying transcriptional programme. This cluster contained known FAE- (Anxa10, Ccl20, Psg18 and Ubd) and M-cell-specific (Gp2) genes, suggesting that the others were novel FAE-specific genes. Some of these novel candidate genes were expressed highly by the FAE and M cells (Calcb, Ces3b, Clca2 and Gjb2), and others only by the FAE (Ascl2, Cftr, Fgf15, Gpr133, Kcna1, Kcnj15, Mycl1, Pgap1 and Rps6kl). We also identified a subset of novel FAE-related genes that were induced in the intestinal epithelium after receptor activator of nuclear factor (NF)-κB ligand stimulation. These included Mfge8 which was specific to FAE enterocytes. This study provides new insight into the FAE transcriptome. Further characterization of the candidate genes identified here will aid the identification of novel regulators of cell function in the FAE.
  • D. S. Donaldson, A. Kobayashi, H. Ohno, H. Yagita, I. R. Williams, N. A. Mabbott
    MUCOSAL IMMUNOLOGY 5 2 216 - 225 2012年03月 [査読有り][通常論文]
     
    Many prion diseases are orally acquired. Our data show that after oral exposure, early prion replication upon follicular dendritic cells (FDC) in Peyer's patches is obligatory for the efficient spread of disease to the brain (termed neuroinvasion). For prions to replicate on FDC within Peyer's patches after ingestion of a contaminated meal, they must first cross the gut epithelium. However, the mechanism through which prions are conveyed into Peyer's patches is uncertain. Within the follicle-associated epithelium overlying Peyer's patches are microfold cells (M cells), unique epithelial cells specialized for the transcytosis of particles. We show that following M cell-depletion, early prion accumulation upon FDC in Peyer's patches is blocked. Furthermore, in the absence of M cells at the time of oral exposure, neuroinvasion and disease development are likewise blocked. These data suggest M cells are important sites of prion uptake from the gut lumen into Peyer's patches.
  • Neil A. Mabbott, J. Kenneth Baillie, Atsushi Kobayashi, David S. Donaldson, Hitoshi Ohmori, Sun-Ok Yoon, Arnold S. Freedman, Tom C. Freeman, Kim M. Summers
    IMMUNOLOGY 133 4 482 - 498 2011年08月 [査読有り][通常論文]
     
    Follicular dendritic cells (FDC) are an important subset of stromal cells within the germinal centres of lymphoid tissues. They are specialized to trap and retain antigen-containing immune complexes on their surfaces to promote B-cell maturation and immunoglobulin isotype class-switching. However, little is known of the cell types from which FDC originate. To address fundamental questions associated with the relationships between FDC and other cell populations, we took advantage of the growing body of publicly available data for transcriptome analysis. We obtained a large number of gene expression data files from a range of different primary mouse cells and cell lines and subjected these data to network-based cluster analysis using BIOLAYOUT EXPRESS(3D). Genes with related function clustered together in distinct regions of the graph and enabled the identification of transcriptional networks that underpin the functional activity of distinct cell populations. Several gene clusters were identified that were selectively expressed by cells of mesenchymal lineage and contained classic mesenchymal cell markers and extracellular matrix genes including various collagens, Acta2, Bgn, Fbn1 and Twist1. Our analysis showed that FDC also express highly many of these mesenchyme-associated genes. Promoter analysis of the genes comprising the mesenchymal clusters identified several regulatory motifs that are binding sites for candidate transcription factors previously known to be candidate regulators of mesenchyme-specific genes. Together, these data suggest FDC are a specialized mesenchymal cell population within the germinal centres of lymphoid tissues.
  • Atsushi Kobayashi, Kenta Mizukoshi, Yasushi Iwasaki, Hajime Miyata, Yasuji Yoshida, Tetsuyuki Kitamoto
    AMERICAN JOURNAL OF PATHOLOGY 178 3 1309 - 1315 2011年03月 [査読有り][通常論文]
     
    The genotype (M/M, M/V, or V/V) at polymorphic codon. 129 of the human prion protein (PrP) gene and the type (1 or 2) of protease-resistant PrP (PrPres) in the brain are major determinants of the clinico pathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). According to this molecular typing system, sCJD has been classified into six subgroups (MM1, MM2, MV1, MV2, VV1, and VV2). Besides these pure subgroups, mixed cases presenting mixed neuropathological phenotypes and more than one PrPres type have been found in sCJD. To investigate the frequency of the co-occurrence of types 1 and 2 PrPres in sCJD patients classified as MM1., we produced type 2 PrPres-specific antibody Tohoku 2 (T2) that can specifically detect the N-terminal cleavage site of type 2 PrPres after protease treatment and examined brain samples from 23 patients with sCJD-MM1. Western blot analysis using the T2 antibody revealed that the minority type 2 PrPres could be detected in all sCJD-MM1 brain samples including those of the cerebellum where sCJD-MM2 prions rarely accumulate. These results show that the co-occurrence of types 1 and 2 PrPres within a single sCJD-MM1 patient is a universal phenomenon. The general co-occurrence of multiple PrPres fragments within a single prion strain questions the validity of the conventional molecular typing system. (Am J Pathol 2011, 178:1309-1315; DOI: 10.1016/j.ajpath.2010.11.069)
  • Atsushi Kobayashi, Nobuyuki Sakuma, Yuichi Matsuura, Shirou Mohri, Adriano Aguzzi, Tetsuyuki Kitamoto
    JOURNAL OF VIROLOGY 84 7 3230 - 3238 2010年04月 [査読有り][通常論文]
     
    The clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD) correlate with the allelo-types (M or V) of the polymorphic codon 129 of the human prion protein (PrP) gene and the electrophoretic mobility patterns of abnormal prion protein (PrP(Sc)). Transmission of sCJD prions to mice expressing human PrP with a heterologous genotype (referred to as cross-sequence transmission) results in prolonged incubation periods. We previously reported that cross-sequence transmission can generate a new prion strain with unique transmissibility, designated a traceback phenomenon. To verify experimentally the traceback of sCJD-VV2 prions, we inoculated sCJD-VV2 prions into mice expressing human PrP with the 129M/M genotype. These 129M/M mice showed altered neuropathology and a novel PrPSc type after a long incubation period. We then passaged the brain homogenate from the 129M/M mouse inoculated with sCJD-VV2 prions into other 129M/M or 129V/V mice. Despite cross-sequence transmission, 129V/V mice were highly susceptible to these prions compared to the 129M/M mice. The neuropathology and PrP(Sc) type of the 129V/V mice inoculated with the 129M/M mouse-passaged sCJD-VV2 prions were identical to those of the 129V/V mice inoculated with sCJD-VV2 prions. Moreover, we generated for the first time a type 2 PrP(Sc)-specific antibody in addition to type 1 PrP(Sc)-specific antibody and discovered that drastic changes in the PrP(Sc) subpopulation underlie the traceback phenomenon. Here, we report the first direct evidence of the traceback in prion infection.
  • Masaki Hizume, Atsushi Kobayashi, Hidehiro Mizusawa, Tetsuyuki Kitamoto
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 391 4 1681 - 1686 2010年01月 [査読有り][通常論文]
     
    Prion protein (PrP) is a glycosylphosphatidylinositol (GPI)-anchored protein, and the C-terminal GPI anchor signal sequence (GPI-SS) of PrP is cleaved before GPI anchoring. However, mutations near the GPI anchor attachment site (the omega site) in the GPI-SS have been recognized in human genetic prion diseases. Moreover, the omega site of PrP has not been identified except hamster, though it is known that amino acid restrictions are very severe at the omega and omega + 2 sites in other GPI-anchored proteins. To investigate the effect of mutations near the omega site of PrP on the conversion and the GPI anchoring, and to discover the omega site of murine PrP, we systematically created mutant murine PrP with all possible single amino acid substitutions at every amino acid residue from codon 228 to 240. We transfected them into scrapie-infected mouse neuroblastoma cells and examined the conversion efficiencies and the GPI anchoring of each mutant PrP. Mutations near the omega site altered the conversion efficiencies and the GPI anchoring efficiencies. Especially, amino acid restrictions for the conversion and the GPI anchoring were severe at codons 230 and 232 in murine PrP, though they were less severe than in other GPI-anchored proteins. Only the Mutant PrPs presented on a cell Surface via a GPI anchor were conversion competent. The present study shows that Mutations in the GPI-SS can affect the GPI anchoring and the conversion efficiency of PrP. We clarified for the first time the omega site of murine PrP and the amino acid conditions near the omega site for the conversion as well as GPI anchoring. (C) 2009 Elsevier Inc. All rights reserved.
  • Atsushi Kobayashi, Masahiro Asano, Shirou Mohri, Tetsuyuki Kitamoto
    NEUROPATHOLOGY 29 5 619 - 624 2009年10月 [査読有り][通常論文]
     
    The transmission of prions to animals with incongruent prion protein (PrP) gene (referred to as cross-sequence transmission) results in a relatively long incubation period and can generate a new prion strain with unique transmissibility designated as a traceback phenomenon. For example, cross-sequence transmission of bovine spongiform encephalopathy (BSE) prions to human generated variant Creutzfeldt-Jakob disease (vCJD) prions which retained the transmissibility to mice expressing bovine PrP. This finding suggests that traceback studies could enable us to identify the origin of prions. There are two distinct phenotypes in dura mater graft-associated Creutzfeldt-Jakob disease (dCJD), with the majority represented by a non-plaque-type of dCJD (np-dCJD) and the minority by a plaque-type of dCJD (p-dCJD). To identify the origin of p-dCJD, we performed a traceback study using mice expressing human PrP with methionine homozygosity (129M/M) or valine homozygosity (129V/V) at polymorphic codon 129. The characteristics of p-dCJD such as the accumulation of abnormal isoform of PrP (PrPSc) intermediate in size between type 1 and type 2, and plaque-type PrP deposition in the brain were maintained after transmission to the 129M/M mice. Furthermore, the 129V/V mice were more susceptible to p-dCJD prions than the 129M/M mice and produced type 2 PrPSc that were identical in size to those from the 129V/V mice inoculated with sporadic CJD prions from a patient with 129V/V and type 2 PrPSc (sCJD-VV2). In addition, we performed intracerebral transmission of sCJD-VV2 prions to the 129M/M mice as an experimental model for p-dCJD. These 129M/M mice showed the accumulation of the intermediate type PrPSc and plaque-type PrP deposition in the brain. These results suggest that p-dCJD could be caused by cross-sequence transmission of sCJD-VV2 prions to individuals with the 129M/M genotype.
  • Chihiro Hiraga, Atsushi Kobayashi, Tetsuyuki Kitamoto
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 382 4 715 - 719 2009年05月 [査読有り][通常論文]
     
    The human prion protein (PrP) has five copies of an octapeptide repeat (OR). The mutant PrP with 6-14 OR causes the genetic form of Creutzfeldt-Jakob disease (CJD). To determine the influence of OR on the conversion of PrP, we examined the conversion efficiency of mouse mutant PrP molecules with 1-16 OR in scrapie-infected cells. The expression level of mutant PrP and the glycoform ratio of the abnormal isoform of PrP (PrP(Sc)) were affected by the number of OR. The conversion efficiency was almost equivalent among mutant PrP molecules with 5-16 OR, whereas that of mutant PrP with 1-4 OR was decreased. The present study suggests that CJD patients with the longer extra OR, who usually show only a trace of PrP(Sc) in the brain, can produce the authentic triplet PrP(Sc) if secondary prion infection occurs. (C) 2009 Elsevier Inc. All rights reserved.
  • Masaki Hizume, Atsushi Kobayashi, Kenta Teruya, Hiroaki Ohashi, James W. Ironside, Shirou Mohri, Tetsuyuki Kitamoto
    JOURNAL OF BIOLOGICAL CHEMISTRY 284 6 3603 - 3609 2009年02月 [査読有り][通常論文]
     
    Prion protein gene (PRNP) E219K is a human polymorphism commonly occurring in Asian populations but is rarely found in patients with sporadic Creutzfeldt-Jakob disease (CJD). Thus the polymorphism E219K has been considered protective against sporadic CJD. The corresponding mouse prion protein (PrP) polymorphism variant (mouse PrP 218K) is not converted to the abnormal isoform (PrPSc) and shows a dominant negative effect on wild-type PrP conversion. To define the conversion activity of this human molecule, we herein established knock-in mice with human PrP 219K and performed a series of transmission experiments with human prions. Surprisingly, the human PrP 219K molecule was converted to PrPSc in variant CJD infection, and the conversion occurred more efficiently than PrP 219E molecule. Notably the knock-in mice with PRNP codon 219E/K showed the least efficient conversion compared with their hemizygotes with PRNP codon 219E/0 or codon 219K/0, or homozygotes with PRNP codon 219E/E or codon 219K/K. This phenomenon indicated heterozygous inhibition. This heterozygous inhibition was observed also in knock-in mice with PRNP codon 129M/V genotype. In addition to variant CJD infection, the human PrP 219K molecule is conversion-competent in transmission experiments with sporadic CJD prions. Therefore, the protective effect of PRNP E219K against sporadic CJD might be due to heterozygous inhibition.
  • Atsushi Kobayashi, Masaki Hizume, Kenta Teruya, Shirou Mohri, Tetsuyuki Kitamoto
    PRION 3 1 27 - 30 2009年01月 [査読有り][通常論文]
     
    The human PrP gene (PRNP) has two major polymorphic codons: 129 for methionine (M) or valine (V) and 219 for glutamate (E) or lysine (K). The PRNP heterozygotes appear to be protected from sporadic CJD compared to the PRNP homozygotes. The molecular mechanism responsible for these protective effects of PRNP heterozygosity has remained elusive. In this review, we describe the inhibition of PrP conversion observed in a series of transmission studies using PRNP heterozygous animal models. In vCJD infection, the conversion incompetent human PrP 129V molecules showed an inhibitory effect on the conversion of human PrP 129M molecules in the 129M/V heterozygous mice. Furthermore, though the human PrP 219E and PrP 219K were both conversion competent in vCJD infection, these conversion competent PrP molecules showed an inhibitory effect in the 219E/K heterozygous animals. To explain this heterozygous inhibition, we propose a possible mechanism designated as the stone fence model.
  • Atsushi Kobayashi, Kunimasa Arima, Masafumi Ogawa, Miho Murata, Takahiro Fukuda, Tetsuyuki Kitamoto
    ACTA NEUROPATHOLOGICA 116 5 561 - 566 2008年11月 [査読有り][通常論文]
     
    Plaque-type deposition of prion protein (PrP) in the brain has been extremely rare in sporadic Creutzfeldt-Jakob disease patients with methionine homozygosity at polymorphic codon 129 of the PrP gene and type 1 abnormal isoform of PrP (sCJD-MM1). Here we report three sCJD-MM1 patients who showed prominent PrP-positive amyloid plaques in the cerebral and cerebellar white matter. All three patients showed clinical courses of long duration (2 years <=), particularly at the end-stage. The white matter of these patients was severely damaged because of the prolonged disease duration. Furthermore, Alzheimer's amyloid precursor protein, which accumulates within the axonal swellings under pathological conditions, co-accumulated with the PrP-amyloid plaques. These findings suggest that the axonal damage reflecting the prolonged disease duration causes the deposition of PrP-amyloid plaques in the white matter. The present study shows that PrP-amyloid plaques can occur in the white matter of sCJD-MM1 cases.
  • Shino Ikeda, Atsushi Kobayashi, Tetsuyuki Kitamoto
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 369 4 1195 - 1198 2008年05月 [査読有り][通常論文]
     
    Prion protein (PrP) contains two N-linked glycosylation sites. It is unknown which amino acid substitution contributes most efficiently to the abolishment of N-linked glycosylations. To define the influence of amino acid substitution at the N-linked glycosylation sites on the conversion efficiency of mouse PrP, we tested each of all 19 amino acid substitutions at either one of the Winked glycosylation sites (codon 180, 182, 196 or 198). The conversion efficiency of the mutagenized PrP was highly dependent on the newly introduced amino acid itself regardless of the absence of Winked glycosylation in scrapie-infected mouse neuroblastoma cells. The majority of mutant PrP with substitutions at the Asn residues of the Winked glycosylation sites were conversion-competent, whereas most mutant PrP with substitutions at the Thr residues were conversion-incompetent. These findings emphasize that the Asn residues of the N-linked glycosylation sites are replaceable to abolish Winked glycosylations without directly affecting the protein function. (C) 2008 Elsevier Inc. All rights reserved.
  • Atsushi Kobayashi, Masahiro Asano, Shirou Mohri, Tetsuyuki Kitamoto
    JOURNAL OF BIOLOGICAL CHEMISTRY 282 41 30022 - 30028 2007年10月 [査読有り][通常論文]
     
    The genotype ( methionine or valine) at polymorphic codon 129 of the human prion protein (PrP) gene and the type ( type 1 or type 2) of abnormal isoform of PrP ( PrPSc) are major determinants of the clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). Here we found that the transmission of sCJD prions from a patient with valine homozygosity (129V/V) and type 2 PrPSc (sCJD-VV2 prions) to mice expressing human PrP with methionine homozygosity (129M/M) generated unusual PrPSc intermediate in size between type 1 and type 2. The intermediate type PrPSc was seen in all examined dura mater graft-associated CJD cases with 129M/M and plaque-type PrP deposits (p-dCJD). p-dCJD prions and sCJD-VV2 prions exhibited similar transmissibility and neuropathology, and the identical type of PrPSc when inoculated into PrP-humanized mice with 129M/M or 129V/V. These findings suggest that p-dCJD could be caused by cross-sequence transmission of sCJD-VV2 prions.
  • A Kobayashi, S Satoh, JW Ironside, S Mohri, T Kitamoto
    JOURNAL OF GENERAL VIROLOGY 86 Pt1 237 - 240 2005年01月 [査読有り][通常論文]
     
    In Creutzfeldt-Jakob disease (CJD), the type (type 1 or 2) of abnormal isoform of the prion protein (PrPSc) in the brain and the genotype at codon 129 of the PrP gene are major determinants of clinicopathological phenotype. Little is known about the difference in biochemical properties between the two types of PrPSc, except for the different proteinase K cleavage sites. To investigate the size of aggregates formed by PrPSc types 1 and 2, brain homogenates from various cases of CJD with the same genotype (homozygous for methionine at codon 129) were passed through filters with a mean pore size of 72 +/- 4 nm. Type 2 PrPSc was efficiently removed from the filtrates by the filters, in contrast to type 1. Even type 2 PrPSc from a patient without amyloid plaques was removed more efficiently than type 1 from patients with amyloid plaques. These results indicate that type 2 PrPSc has a larger aggregation size than type 1, irrespective of the existence of amyloid plaques.
  • A Kobayashi, S Katagiri, T Kimura, K Ochiai, T Umemura
    JOURNAL OF VETERINARY MEDICAL SCIENCE 64 9 773 - 777 2002年09月 [査読有り][通常論文]
     
    The direct effects of three steroid hormones (progesterone, estradiol-17beta and corticosterone) on the growth of Neospora caninum (N. caninum) tachyzoite were examined in Vero cells. Subsequently, ovariectomized BALB/c mice infected with N. caninum were treated with physiological concentrations of the steroid hormones for I or 2 weeks. These hormones had no direct effect on the parasite growth in vitro. In the infected mice, there was no significant difference in the parasite distribution and histopathological changes between the hormone-injected and control groups. No mice showed parasitemia at the time of autopsy. These results suggest that physiological levels of steroid hormones (progesterone, estradiol- 17beta and corticosterone) do not reactivate N. caninum in mice.

書籍

  • Kobayashi A, Kitamoto T, Mizusawa H (担当:共著範囲:Chapter 12. Iatrogenic Creutzfeldt-Jakob disease.)
    Elsevier. 2018年06月 (ISBN: 9780444639455) 498 207-218 
    Kobayashi A, Kitamoto T, Mizusawa H. Iatrogenic Creutzfeldt-Jakob disease. In: Pocchiari M, Manson J, eds. Human Prion Diseases. San Diego: Elsevier BV, 2018: 207-218.
  • Clinical Neuroscience, ニューロジェネティクス新時代-次世代シークエンサーが拓く新しい世界.
    小林篤史 (担当:共著範囲:筋疾患・神経疾患のジェネティクス-プリオン病.)
    中外医学社 2018年02月 36(2): 236-237 
    小林靖編

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    Asian Pacific Prion Symposium 2019 2019年10月 ポスター発表
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    Atsushi Kobayashi, Yasushi Iwasaki, Masaki Takao, Yuko Saito, Toru Iwaki, Shirou Mohri, Tetsuyuki Kitamoto
    Asian Pacific Prion Symposium 2019 2019年10月 口頭発表(一般)
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    第162回日本獣医学会学術集会 2019年09月 口頭発表(一般) 茨城県つくば市
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    EuroCJD meeting 2018 2018年10月 口頭発表(一般) Rome, Italy
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    Atsushi Kobayashi
    19th International Congress of Neuropathology 2018年09月 口頭発表(招待・特別) Tokyo, Japan
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    第36回日本認知症学会学術集会 2017年11月 シンポジウム・ワークショップパネル(指名)
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    Asian Pacific Prion Symposium 2017 2017年10月 口頭発表(招待・特別)
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    第160回日本獣医学会学術集会 2017年09月 口頭発表(一般)
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    PRION2017 2017年05月 口頭発表(招待・特別)
  • Clinical and pathological characterization of “sporadic Creutzfeldt-Jakob disease” with histories of neurosurgery to identify iatrogenic cases  [通常講演]
    Tsuyoshi Hamaguchi, Kenji Sakai, Atsushi Kobayashi, Tetsuyuki Kitamoto, Ryusuke Ae, Yosikazu Nakamura, Nobuo Sanjo, Tadashi Tsukamoto, Hidehiro Mizusawa, Masahito Yamada
    PRION2017 2017年05月 ポスター発表
  • 遺伝性プリオン病の病型毎のPrPScとAβの沈着パターンに関する病理学的解析  [通常講演]
    古川迪子, 三條伸夫, 小林篤史, 浜口毅, 山田正仁, 北本哲之, 水澤英洋, 横田隆徳
    第35回日本認知症学会学術集会 2016年12月 ポスター発表
  • ウマ主要組織適合遺伝子複合体クラスI遺伝子導入マウスのウマヘルペスウイルス1型に対する感受性の検討  [通常講演]
    港江利奈, 青島圭祐, 小林篤史, 木村享史
    第159回日本獣医学会学術集会 2016年09月 口頭発表(一般)
  • Colocalization of Aβ42 with PrPSc-plaques in the brain of the Gerstmann-Sträussler-Scheinker disease with the P105L mutation.  [通常講演]
    Fumiko Furukawa, Nobuo Sanjo, Atsushi Kobayashi, Tsuyoshi Hamaguchi, Masahito Yamada, Tetsuyuki Kitamoto, Hidehiro Mizusawa, Takanori Yokota
    Alzheimer's Association International Conference 2016年07月 ポスター発表
  • Mechanisms of transmission of prion diseases  [招待講演]
    Atsushi Kobayashi
    第57回日本神経学会学術大会 2016年05月 口頭発表(招待・特別)
  • Iatrogenic transmission of Creutzfeldt-Jakob disease  [招待講演]
    Atsushi Kobayashi, Piero Parchi, Masahito Yamada, Paul Brown, Daniela Saverioni, Yuichi Matsuura, Atsuko Takeuchi, Shirou Mohri, Tetsuyuki Kitamoto
    PRION2016 2016年05月 口頭発表(招待・特別)
  • Identification of the origin of Creutzfeldt-Jakob disease after cadaver-sourced pituitary growth hormone treatment using an amplification property in protein misfolding cyclic amplificatiton.  [通常講演]
    Takeuchi A, Yamamoto M, Parchi P, HaïK S, Morita M, Kobayashi A, Kitamoto T
    PRION2016 2016年05月 ポスター発表
  • Differential association of amyloid-β with PrPSc pathology in each genetic prion disease.  [通常講演]
    Fumiko Furukawa, Nobuo Sanjo, Atsushi Kobayashi, Tsuyoshi Hamaguchi, Masahito Yamada, Tetsuyuki Kitamoto, Hidehiro Mizusawa, Takanori Yokota
    PRION2016 2016年05月 ポスター発表
  • ヒト化プリオン蛋白ノックインマウスモデルの有用性 ― 医原性プリオン感染の同定法の確立  [通常講演]
    小林篤史, 山田正仁, 松浦裕一, 毛利資郎, 北本哲之
    第158回日本獣医学会学術集会 2015年09月 口頭発表(一般)
  • Cell-PMCA of acquired Creutzfeldt-Jakob disease  [通常講演]
    Atsuko Takeuchi, Atsushi Kobayashi, Piero Parchi, Masahito Yamada, Masanori Morita, Shuusei Uno, Tetsuyuki Kitamoto
    Asian Pacific Prion Symposium 2015 2015年09月 ポスター発表
  • Neuropathological and biochemical criteria to identify acquired Creutzfeldt-Jakob disease among presumed sporadic cases  [通常講演]
    Atsushi Kobayashi, Masahito Yamada, Yuichi Matsuura, Shirou Mohri, Tetsuyuki Kitamoto
    Asian Pacific Prion Symposium 2015 2015年09月 ポスター発表
  • Amyloid-β42 deposition in the brain of the Gerstmann-Sträussler-Scheinker disease with the P105L mutation.  [通常講演]
    Fumiko Furukawa, Nobuo Sanjo, Atsushi Kobayashi, Tsuyoshi Hamaguchi, Masahito Yamada, Tetsuyuki Kitamoto, Hidehiro Mizusawa, Takanori Yokota
    Asian Pacific Prion Symposium 2015 2015年09月 ポスター発表
  • ゲルストマン・シュトロイスラー・シャインカー病P105L一家系3例でのプリオン、タウ、βアミロイドの免疫組織化学的検討  [通常講演]
    光藤尚, 石澤圭介, 塩田敬, 本間琢, 小林篤史, 小森隆司, 中里良彦, 北本哲之, 佐々木惇, 荒木信夫, 山元敏正
    第56回日本神経病理学会総会学術研究会 2015年06月 ポスター発表
  • プリオン病の感染実験  [招待講演]
    小林 篤史
    第56回日本神経病理学会総会学術研究会 2015年06月 シンポジウム・ワークショップパネル(公募)
  • V180I変異遺伝性クロイツフェルト・ヤコブ病の病理学的、生化学的特徴の解析  [通常講演]
    古川迪子, 三條伸夫, 日詰正樹, 小林篤史, 北本哲之, 山田正仁, 水澤英洋, 横田隆徳
    第56回日本神経学会学術大会 2015年05月 口頭発表(一般)
  • プリオン病 Update  [招待講演]
    小林 篤史
    NeuroCPC 2015年03月 口頭発表(招待・特別)
  • V180I変異遺伝性プリオン病の臨床・病理解析  [通常講演]
    三條伸夫, テムチナ, 日詰正樹, 新竜一郎, 佐藤克也, 小林篤史, 北本哲之, 山田正仁, 水澤英洋
    第33回日本認知症学会学術集会 2014年11月 口頭発表(一般)
  • プリオン蛋白遺伝子コドン105変異(P105L)によるGerstmann-Sträussler- Scheinker 症候群(GSS)の臨床像 ―GSS(P102L)との比較解析―  [通常講演]
    古川迪子, 三條伸夫, 日熊麻耶, 日詰正樹, 小林篤史, 北本哲之, 中村好一, 村山繁雄, 山田正仁, 水澤英洋
    第19回日本神経感染症学会総会学術集会 2014年09月 口頭発表(一般)
  • Distinct origins of dura mater graft-associated Creutzfeldt-Jakob disease: past and future problems.  [通常講演]
    Kobayashi A, Matsuura Y, Mohri S, Kitamoto T
    Asian Pacific Prion Symposium 2014 2014年07月 口頭発表(一般)
  • Involvement of the dorsal root ganglion in GSS with P105L mutation  [通常講演]
    Furukawa F, Sanjo N, Kobayashi A, Shiraishi A, Ishikawa K, Yamada M, Kitamoto T, Eishi Y, Mizusawa H
    Asian Pacific Prion Symposium 2014 2014年07月 口頭発表(一般)
  • 孤発性クロイツフェルト・ヤコブ病MV2の新分類  [通常講演]
    小林篤史, 岩崎靖, 大塚浩之, 山田正仁, 吉田眞理, 松浦裕一, 毛利資郎, 北本哲之
    第55回日本神経病理学会総会学術研究会 2014年06月 ポスター発表
  • 皮質や基底核に及ぶ広範囲な海綿状変性と小脳にkuru斑を認めた孤発性Creutzfeldt-Jakob病MV2型の1剖検例  [通常講演]
    荒木邦彦, 中野雄太, 小林篤史, 松平敬史, 杉浦明, 高尾昌樹, 北本哲之, 村山繁雄, 小尾智一
    第55回日本神経病理学会総会学術研究会 2014年06月 ポスター発表
  • 非プリオン病脳におけるプリオンの凝集について  [通常講演]
    鈴木奈穂美, 浅川美果, 鈴木-香山絵美, 武井洋一, 木下通亨, 小林篤史, 北本哲之, 小柳清光
    第55回日本神経病理学会総会学術研究会 2014年06月 口頭発表(一般)
  • Immunohistochemical and neuropathological analyses of the prion protein in genetic Creutzfeldt-Jakob disease with V180I mutation.  [通常講演]
    Hizume M, Sanjo N, Satoh K, Hamaguchi T, Yamada M, Iwasaki Y, Kobayashi A, Kitamoto T, Mizusawa H
    PRION 2014 2014年05月 ポスター発表
  • Clinical features of Gerstmann-Sträussler-Scheinker syndrome with a P105L mutation and a valine-encoding polymorphic codon 129 in the prion protein gene.  [通常講演]
    Furukawa F, Sanjo N, Kobayashi A, Kitamoto T, Shiraishi A, Ishikawa K, Honda H, Yamada M, Mizusawa H
    PRION 2014 2014年05月 ポスター発表
  • Further characterization of PK-resistant PrPsc core fragments in sporadic CJD brains carrying VV or MV at PRNP codon 129  [通常講演]
    Saverioni D, Capellari S, Kobayashi A, Kitamoto T, Parchi P
    PRION 2014 2014年05月 ポスター発表
  • Immunohistochemical and neuropathological analyses of the prion protein in genetic Creutzfeldt-Jakob disease with V180I mutation.  [通常講演]
    PRION 2014 2014年 ポスター発表
  • Clinical features of Gerstmann-Sträussler-Scheinker syndrome with a P105L mutation and a valine-encoding polymorphic codon 129 in the prion protein gene.  [通常講演]
    PRION 2014 2014年 ポスター発表
  • Further characterization of PK-resistant PrPsc core fragments in sporadic CJD brains carrying VV or MV at PRNP codon 129  [通常講演]
    PRION 2014 2014年 ポスター発表
  • 孤発性クロイツフェルト・ヤコブ病MV2の新分類  [通常講演]
    日本神経病理学会総会学術研究会 2014年 ポスター発表
  • 皮質や基底核に及ぶ広範囲な海綿状変性と小脳にkuru斑を認めた孤発性Creutzfeldt-Jakob病MV2型の1剖検例  [通常講演]
    日本神経病理学会総会学術研究会 2014年 ポスター発表
  • プリオン蛋白遺伝子コドン105変異(P105L)によるGerstmann-Sträussler- Scheinker 症候群(GSS)の臨床像 ―GSS(P102L)との比較解析―  [通常講演]
    日本神経感染症学会総会学術集会 2014年 ポスター発表
  • V180I変異遺伝性プリオン病の臨床・病理解析  [通常講演]
    日本認知症学会学術集会 2014年
  • Revision of Sporadic Creutzfeldt-Jakob Disease with MV2 prions  [通常講演]
    Asian Pacific Prion Symposium 2013 2013年 ポスター発表
  • Revision of Sporadic Creutzfeldt-Jakob Disease with MV2 prions  [通常講演]
    Asian Pacific Prion Symposium 2013 2013年 ポスター発表
  • 脊髄円錐・馬尾に病変を認めた抗アクアポリン4抗体陽性視神経脊髄炎の2症例  [通常講演]
    高井良樹, 三須建郎, 中島一郎, 高橋利幸, 小林篤史, 北本哲之, 藤原一男, 糸山泰人
    第52回日本神経学会学術大会 2011年05月 口頭発表(一般)
  • Experimental verification of a traceback phenomenon in prion infection  [通常講演]
    Asia-Oceania Symposium on Prion Diseases 2010年
  • Histidine residues in octapeptide repeats are not essential for the conversion of PrP  [通常講演]
    Asia-Oceania Symposium on Prion Diseases 2010年 ポスター発表
  • Experimental verification of a traceback phenomenon in prion infection  [通常講演]
    Asia-Oceania Symposium on Prion Diseases 2010年
  • Histidine residues in octapeptide repeats are not essential for the conversion of PrP  [通常講演]
    Asia-Oceania Symposium on Prion Diseases 2010年 ポスター発表
  • ヒト異常型プリオン蛋白特異的抗体の作製  [通常講演]
    2009年 プリオン研究会 2009年 ポスター発表
  • ヒト異常型プリオン蛋白特異的抗体の作製  [通常講演]
    2009年 プリオン研究会 2009年 ポスター発表
  • 硬膜移植後CJDの感染源  [招待講演]
    小林 篤史
    第49回日本神経病理学会総会学術研究会 2008年05月 シンポジウム・ワークショップパネル(公募)
  • Cross-sequence transmission of sporadic Creutzfeldt-Jakob disease creates a new prion strain  [通常講演]
    Transmissible Spongiform Encephalopathies The definitive American TSE Meeting 2008年 ポスター発表
  • プリオン蛋白中のオクタペプチドリピート数が異常化に及ぼす影響  [通常講演]
    2008年プリオン研究会 2008年 ポスター発表
  • プリオン蛋白遺伝子のGPIアンカーシグナル配列における1アミノ酸置換と配列の長さがプリオン蛋白の異常化効率に与える影響  [通常講演]
    2008年プリオン研究会 2008年 ポスター発表
  • Cross-sequence transmission of sporadic Creutzfeldt-Jakob disease creates a new prion strain  [通常講演]
    Transmissible Spongiform Encephalopathies The definitive American TSE Meeting 2008年 ポスター発表
  • プリオン蛋白中のオクタペプチドリピート数が異常化に及ぼす影響  [通常講演]
    2008年プリオン研究会 2008年 ポスター発表
  • プリオン蛋白遺伝子のGPIアンカーシグナル配列における1アミノ酸置換と配列の長さがプリオン蛋白の異常化効率に与える影響  [通常講演]
    2008年プリオン研究会 2008年 ポスター発表
  • 孤発性クロイツフェルト・ヤコブ病プリオンのcross-sequence transmissionは新たなプリオン株を生み出す  [通常講演]
    プリオン研究会 2007年 ポスター発表
  • 219Lysプリオン蛋白はvCJD感染において簡単に異常化する  [通常講演]
    プリオン研究会 2007年 ポスター発表
  • PrP異常化に対するN-結合型糖鎖結合部位のアミノ酸置換の影響  [通常講演]
    プリオン研究会 2007年 ポスター発表
  • 孤発性クロイツフェルト・ヤコブ病プリオンのcross-sequence transmissionは新たなプリオン株を生み出す  [通常講演]
    プリオン研究会 2007年 ポスター発表
  • 219Lysプリオン蛋白はvCJD感染において簡単に異常化する  [通常講演]
    プリオン研究会 2007年 ポスター発表
  • PrP異常化に対するN-結合型糖鎖結合部位のアミノ酸置換の影響  [通常講演]
    プリオン研究会 2007年 ポスター発表
  • Type 1 and type 2 human PrPSc have different aggregation sizes in methionine homozygotes with sporadic, iatrogenic and variant Creutzfeldt-Jakob disease  [通常講演]
    International symposium PRION DISEASES 2004年 ポスター発表
  • Type 1 and type 2 human PrPSc have different aggregation sizes in methionine homozygotes with sporadic, iatrogenic and variant Creutzfeldt-Jakob disease  [通常講演]
    International symposium PRION DISEASES 2004年 ポスター発表

その他活動・業績

特許

  • 特開2011-46698:変異タンパク質の製造方法  2011年03月10日
    北本哲之, 堂浦克美, 小林篤史, 照屋健太, 竹内敦子, 森田将典, 山本幸, 白澤映子
  • 特開WO/2008/099451:網羅的アミノ酸置換による高機能蛋白の設計方法  2008年08月21日
    北本哲之, 小林篤史, 浅野昌宏

受賞

  • 2020年09月 The Journal of Veterinary Medical Science 2019年度 Good Reviewer 賞
     
    受賞者: 小林篤史
  • 2016年01月 東北大学医学部 平成27年度医学部奨学賞銀賞
     獲得性クロイツフェルト・ヤコブ病の確定診断法の確立 
    受賞者: 小林篤史
  • 2016年01月 公益社団法人 宮城県医師会 平成27年度医学奨励賞
     獲得性クロイツフェルト・ヤコブ病の確定診断法の確立 
    受賞者: 小林篤史
  • 2010年05月 艮陵医学振興会 平成22年度匂坂記念賞
     プリオン病感染防止へ向けた基礎的研究―プリオン病の感染源同定法の確立 
    受賞者: 小林篤史
  • 2008年08月 プリオン研究会 2008年ベストポスター賞
     プリオン蛋白遺伝子のGPIアンカーシグナル配列における1アミノ酸置換と配列の長さがプリオン蛋白の異常化に与える影響 
    受賞者: 日詰正樹;小林篤史;水澤英洋;北本哲之
  • 2007年08月 プリオン研究会 2007年ベストポスター賞
     孤発性クロイツフェルト・ヤコブ病プリオンのcross-sequence transmissionは新たなプリオン株を生みだす 
    受賞者: 小林篤史;浅野昌宏;毛利資郎;北本哲之

共同研究・競争的資金等の研究課題

  • プリオン感染リスクの網羅的解析
    公益財団法人 武田科学振興財団:2020年度医学系研究助成
    研究期間 : 2020年11月 -2022年03月
  • ブタのPD-1/PD-L1を介した免疫抑制機序の解析と新規抗体薬の開発
    北海道大学大学院獣医学研究院:2020年度臨床研究推進研究費
    研究期間 : 2020年07月 -2021年03月 
    代表者 : 岡川朋弘, 栁川洋二郎, 小林篤史
  • 末梢からのプリオン感染リスクの網羅的解析
    公益財団法人 日立財団:2019年度倉田奨励金
    研究期間 : 2020年04月 -2021年03月
  • 鼻疽菌潜伏感染場の摘発に向けた新規血清診断法の開発
    日本中央競馬会:平成31年度日本中央競馬会畜産振興事業
    研究期間 : 2019年04月 -2021年03月 
    代表者 : 木村享史
  • プリオン蛋白の異常化機構解明研究
    日本学術振興会:科学研究費補助金 基盤研究(C)
    研究期間 : 2018年04月 -2020年03月 
    代表者 : 小林 篤史
  • プリオン病におけるプリオンメカニズムの解明
    公益信託加藤記念難病研究助成基金:第32回(平成30年度)研究助成
    研究期間 : 2018年10月 -2019年09月 
    代表者 : 小林 篤史
  • GPIアンカーのシアル化が遺伝性プリオン病を引き起こすのか?
    公益財団法人 寿原記念財団:第32回研究助成
    研究期間 : 2018年04月 -2019年03月 
    代表者 : 小林 篤史
  • プリオン蛋白GPIアンカーのシアル化が遺伝性プリオン病を引き起こすのか?
    公益財団法人 金原一郎記念医学医療振興財団:第32回基礎医学医療研究助成金
    研究期間 : 2017年11月 -2018年10月 
    代表者 : 小林 篤史
  • 成熟プリオン蛋白には存在しないアミノ酸変異がプリオン蛋白異常化をおこす機序の解明
    日本学術振興会:科学研究費助成事業(学術研究助成基金助成金) 若手(B)
    研究期間 : 2016年04月 -2018年03月 
    代表者 : 小林 篤史
  • GPIアンカリング不全がプリオン蛋白の異常化を引き起こすか?
    公益財団法人 武田科学振興財団:2016年度医学系研究奨励
    研究期間 : 2016年11月 -2017年10月 
    代表者 : 小林 篤史
  • プリオン病自然発病モデル動物を利用したプリオン蛋白異常化メカニズムの研究
    公益財団法人 秋山記念生命科学振興財団:2016年度研究助成<一般>
    研究期間 : 2016年09月 -2017年09月 
    代表者 : 小林 篤史
  • 獲得性プリオン病の診断法の開発
    公益財団法人 難病医学研究財団:平成27年度医学研究奨励助成金
    研究期間 : 2016年01月 -2017年03月 
    代表者 : 小林 篤史
  • 難治性疾患実用化研究事業 「プリオン病及び遅発性ウイルス感染症の分子病態解明・治療法開発に関する調査研究」 研究分担者
    日本医療研究開発機構:日本医療研究開発機構研究費
    研究期間 : 2015年04月 -2017年03月 
    代表者 : 山田 正仁
  • 難治性疾患等政策研究事業 「プリオン病及び遅発性ウイルス感染症に関する調査研究」 研究分担者
    厚生労働省:厚生労働科学研究費補助金
    研究期間 : 2014年04月 -2015年03月 
    代表者 : 山田 正仁
  • プリオン病自然発病モデル動物を用いたプリオン蛋白異常化メカニズムの研究
    三菱財団:自然科学研究助成
    研究期間 : 2010年04月 -2013年03月 
    代表者 : 北本 哲之
  • 濾胞樹状細胞からのプリオン神経侵入経路の解明
    文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2010年 -2012年 
    代表者 : 小林 篤史, 竹内 敦子
  • 難治性疾患克服研究事業 「プリオン病及び遅発性ウイルス感染症に関する調査研究」 研究分担者
    厚生労働省:厚生労働科学研究費補助金
    研究期間 : 2008年04月 -2010年03月 
    代表者 : 山田 正仁
  • トレースバック実験によるプリオンの由来の同定
    文部科学省:科学研究費補助金(若手研究(B))
    研究期間 : 2008年 -2009年 
    代表者 : 小林 篤史
  • 難治性疾患克服研究事業 「プリオン病及び遅発性ウイルス感染症に関する調査研究」 研究分担者
    厚生労働省:厚生労働科学研究費補助金
    研究期間 : 2006年04月 -2007年03月 
    代表者 : 水澤 英洋
  • 培養細胞を用いたPMCA法によるヒトプリオンの増幅
    文部科学省:科学研究費補助金(若手研究(スタートアップ))
    研究期間 : 2006年 -2007年 
    代表者 : 小林 篤史

教育活動情報

主要な担当授業

  • 先端獣医科学特論B 獣医病理学特論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学研究科
  • 一般教育演習(フレッシュマンセミナー)
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 全学教育
    キーワード : 動物、ヒト、病気、病因、病態、病理、症状、予防、治療
  • 先端獣医科学特論A 国際獣医科学特論:臨床獣医学
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学研究科
  • 病理学総論実習
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 獣医学部
    キーワード : 動物病理学,病理解剖,病理組織学,細胞傷害,細胞・組織の適応,循環障害,炎症,腫瘍
  • 獣医科学基礎科目 臨床疾病学特論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学院
  • 病理学各論実習
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 獣医学部
    キーワード : 疾患,病理学,診断学
  • 先端獣医科学科目 獣医病理学特論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学院
  • 総合専門臨床特論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 獣医学院
  • 獣医病理診断学演習
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 獣医学部
  • アドバンスト演習
    開講年度 : 2018年
    課程区分 : 学士課程
    開講学部 : 獣医学部

大学運営

委員歴

  • 2020年04月 - 現在   日本神経感染症学会   評議員
  • 2015年09月 - 現在   Asian Pacific Society of Prion Research   評議員
  • 2020年04月 - 2022年03月   獣医学研究院   学術交流事業委員会委員
  • 2020年04月 - 2022年03月   獣医学部   学術情報委員会委員
  • 2020年04月 - 2022年03月   獣医学部   学習管理システム委員会委員
  • 2020年04月 - 2022年03月   獣医学研究院   教務委員会委員
  • 2020年04月 - 2022年03月   北海道大学 図書館委員会委員
  • 2018年08月 - 2022年03月   北海道大学   学生相談総合センター運営委員会委員
  • 2018年02月 - 2022年03月   獣医学部   獣医学教育改革室運営委員会委員
  • 2018年04月 - 2020年03月   獣医学研究院   共同利用機器施設運営委員会委員
  • 2018年04月 - 2020年03月   獣医学部 ポータルサイト委員会委員
  • 2016年11月 - 2020年03月   獣医学研究院   動物実験委員会委員
  • 2018年04月 - 2019年03月   獣医学研究院   広報委員会委員
  • 2017年04月 - 2019年03月   北海道大学   高等教育研究専門委員会委員
  • 2017年04月 - 2019年03月   獣医学研究院   国際交流委員会委員
  • 2016年04月 - 2019年03月   獣医学部   共用試験委員会委員
  • 2016年04月 - 2018年03月   獣医学研究院   獣医標本施設運営委員会委員
  • 2016年04月 - 2018年03月   北海道大学   動物実験委員会委員
  • 2015年04月 - 2017年03月   日本医療研究開発機構   日本医療研究開発機構研究費 難治性疾患実用化研究事業 「プリオン病及び遅発性ウイルス感染症の分子病態解明・治療法開発に関する調査研究」班員
  • 2015年04月 - 2017年03月   獣医学研究科   FD委員会委員
  • 2006年04月 - 2015年03月   厚生労働省   厚生労働科学研究費補助金 難治性疾患克服研究事業 「プリオン病及び遅発性ウイルス感染症に関する調査研究」班員


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