研究者データベース

中村 秀樹(ナカムラ ヒデキ)
医学研究院 連携研究センター
助手

基本情報

所属

  • 医学研究院 連携研究センター

職名

  • 助手

学位

  • 医学博士(北海道大学)

J-Global ID

研究キーワード

  • 免疫   皮膚病理学   超微形態   細胞・組織   動物   

研究分野

  • ライフサイエンス / 皮膚科学

研究活動情報

論文

  • Shota Takashima, Satoru Shinkuma, Yasuyuki Fujita, Ken Natsuga, Toshifumi Nomura, Tokimasa Hida, Shuku Ishikawa, Hideki Nakamura, Riichiro Abe, Hiroshi Shimizu
    The Journal of dermatology 45 9 e260-e261 - e261 2018年09月 [査読有り][通常論文]
  • Daisuke Shimbo, Takeo Abumiya, Kota Kurisu, Toshiya Osanai, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Hideki Nakamura, Hiroshi Shimuzu, Kiyohiro Houkin
    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES 26 12 2994 - 3003 2017年12月 [査読有り][通常論文]
     
    Background: The development of cerebral infarction after transient ischemia is attributed to postischemic delayed hypoperfusion in the microvascular region. In the present study, we assessed the microvascular perfusion capacity of infused liposome-encapsulated hemoglobin (LEH) in a therapeutic approach for transient middle cerebral artery occlusion (tMCAO). Methods: Two-hour middle cerebral artery occlusion rats were immediately subjected to intra-arterial infusion of LEH (LEH group) or saline (vehicle group) or no treatment (control group), and then to recanalization. Neurological findings, infarct and edema progression, microvascular endothelial dysfunction, and inflammatory reactions were compared between the 3 groups after 24 hours of reperfusion. Microvascular perfusion in the early phase of reperfusion was evaluated by hemoglobin immunohistochemistry and transmission electron microscopy. Results: The LEH group achieved significantly better results in all items evaluated than the other groups. Hemoglobin immunohistochemistry revealed that the number of hemoglobin-positive microvessels was significantly greater in the LEH group than in the other groups (P < .01), with microvascular perfusion being more likely in narrow microvessels (<= 5 mu m in diameter). An electron microscopic examination revealed that microvessels in the control group were compressed and narrowed by swollen astrocyte end-feet, whereas those in the LEH group had a less deformed appearance and contained LEH particles and erythrocytes. Conclusion: The results of the present study demonstrated that the infusion of LEH reduced infarctions after tMCAO with more hemoglobin-positive and less deformed microvessels at the early phase of reperfusion, suggesting that the superiority of the microvascular perfusion of LEH mediates its neuroprotective effects.
  • Ken Natsuga, Wataru Nishie, Machiko Nishimura, Satoru Shinkuma, Mika Watanabe, Kentaro Izumi, Hideki Nakamura, Yoshiaki Hirako, Hiroshi Shimizu
    HUMAN MUTATION 38 12 1666 - 1670 2017年12月 [査読有り][通常論文]
     
    Plectin is a linker protein that interacts with intermediate filaments and 4 integrin in hemidesmosomes of the epidermal basement membrane zone (BMZ). Type XVII collagen (COL17) has been suggested as another candidate plectin binding partner in hemidesmosomes. Here, we demonstrate that plectin-COL17 binding helps to maintain epidermal BMZ organization. We identified an epidermolysis bullosa (EB) simplex patient as having markedly diminished expression of plectin and COL17 in skin. The patient is compound heterozygous for sequence variants in the plectin gene (PLEC); one is a truncation and the other is a small in-frame deletion sequence variant. The in-frame deletion is located in the putative COL17-binding domain of plectin and abolishes the plectin-COL17 interaction in vitro. These results imply that disrupted interaction between plectin and COL17 is involved in the development of EB. Our study suggests that protein-protein binding defects may underlie EB in patients with unidentified disease-causing sequence variants.
  • Satoru Shinkuma, Tae Masunaga, Saori Miyawaki, Shota Takashima, Ken Natsuga, Toshifumi Nomura, Yasuyuki Fujita, Hideki Nakamura, Hiroshi Shimizu
    JOURNAL OF DERMATOLOGICAL SCIENCE 88 1 139 - 141 2017年10月 [査読有り][通常論文]
  • Mika Watanabe, Ken Natsuga, Wataru Nishie, Yasuaki Kobayashi, Giacomo Donati, Shotaro Suzuki, Yu Fujimura, Tadasuke Tsukiyama, Hideyuki Ujiie, Satoru Shinkuma, Hideki Nakamura, Masamoto Murakami, Michitaka Ozaki, Masaharu Nagayama, Fiona M. Watt, Hiroshi Shimizu
    ELIFE 6 2017年07月 [査読有り][通常論文]
     
    Type XVII collagen (COL17) is a transmembrane protein located at the epidermal basement membrane zone. COL17 deficiency results in premature hair aging phenotypes and in junctional epidermolysis bullosa. Here, we show that COL17 plays a central role in regulating interfollicular epidermis (IFE) proliferation. Loss of COL17 leads to transient IFE hypertrophy in neonatal mice owing to aberrant Wnt signaling. The replenishment of COL17 in the neonatal epidermis of COL17-null mice reverses the proliferative IFE phenotype and the altered Wnt signaling. Physical aging abolishes membranous COL17 in IFE basal cells because of inactive atypical protein kinase C signaling and also induces epidermal hyperproliferation. The overexpression of human COL17 in aged mouse epidermis suppresses IFE hypertrophy. These findings demonstrate that COL17 governs IFE proliferation of neonatal and aged skin in distinct ways. Our study indicates that COL17 could be an important target of anti-aging strategies in the skin.
  • Suzuki S, Nomura T, Miyauchi T, Takeda M, Nakamura H, Shinkuma S, Fujita Y, Akiyama M, Shimizu H
    The Journal of investigative dermatology 136 10 2093 - 2095 2016年10月 [査読有り][通常論文]
  • Kota Kurisu, Takeo Abumiya, Hideki Nakamura, Daisuke Shimbo, Hideo Shichinohe, Naoki Nakayama, Ken Kazumata, Hiroshi Shimizu, Kiyohiro Houkin
    NEUROSURGERY 79 1 125 - 134 2016年07月 [査読有り][通常論文]
     
    BACKGROUND: Although transarterial regional hypothermia is an attractive alternative to general hypothermia, its efficacy and underlying mechanisms remain unclear. OBJECTIVE: To confirm transarterial regional hypothermia therapeutic effects on ischemia/reperfusion (I/R) injury and to elucidate the mechanisms responsible. METHODS: The therapeutic effects of transarterial regional hypothermia were initially investigated in 2-hour middle cerebral artery occlusion rats regionally infused with 10 degrees C saline (cold saline group) or 37 degrees C saline (warm saline group) and untreated rats (control group) just before the onset of 24 hours of reperfusion. The time course of infarct and edema progression, inflammatory reactions, microvascular morphological changes, and aquaporin-4 (AQP4) expression was analyzed after 0, 2, 6, and 24 hours of reperfusion. RESULTS: Cold saline infusion only lowered brain temperatures for 30 minutes but mediated strong neuroprotective effects with infarct volume reductions of less than one- third. The time-course analysis revealed the following sequence of ischemia/reperfusion injury-related events in the control group: upregulated expression of AQP4 (2 hours); microvascular narrowing resulting from swollen astrocytic end-feet (2-6 hours); infarct and edema progression, blood-brain barrier disruption, and upregulated expression of intracellular adhesion molecule-1 (6-24 hours); and the activation of other inflammatory reactions (24 hours). These sequential events were inhibited in the cold saline group. CONCLUSION: Transarterial regional hypothermia initially inhibited the acute AQP4 surge and then attenuated microvascular narrowing, blood-brain barrier disruption, and activation of other inflammatory reactions, leading to strong neuroprotective effects. More direct and intensive cooling of the endothelium and its surroundings may contribute to these effects.
  • Mayumi Wada, Wataru Nishie, Hideyuki Ujiie, Kentaro Izumi, Hiroaki Iwata, Ken Natsuga, Hideki Nakamura, Yoshimasa Kitagawa, Hiroshi Shimizu
    JOURNAL OF INVESTIGATIVE DERMATOLOGY 136 5 938 - 946 2016年05月 [査読有り][通常論文]
     
    In bullous pemphigoid, the common autoimmune blistering disorder, IgG autoantibodies target various epitopes on hemidesmosomal transmembrane collagen XVII (COL17)/BP180. Antibodies (Abs) targeting the extracellular noncollagenous 16th A domain of COL17 may be pathogenic; however, the pathogenic roles of Abs targeting non-noncollagenous 16th A regions are poorly understood. In this study using a pathogenic and a nonpathogenic monoclonal antibody (mAb) targeting the noncollagenous 16th A domain (mAb TS39-3) and the C-terminus domain (mAb C17-C1), respectively, we show that endocytosis of immune complexes after binding of Abs to cell surface COL17 is a key phenomenon that induces skin fragility. Passive transfer of IgG1 mouse mAb TS39-3 but not mAb C17-C1 induces dermal-epidermal separation in neonatal human COL17-expressing transgenic mice. Interestingly, mAb C17-C1 strongly binds with the dermal-epidermal junction of the recipient mice skin, suggesting that binding of Abs with COL17 is insufficient to induce skin fragility. In cultured normal human epidermal keratinocytes treated with these mAbs, mAb TS39-3 but not mAb C17-C1 internalizes immune complexes after binding with cell surface COL17 via macropinocytosis, resulting in reduced COL17 expression. This study shows that pathogenicity of Abs targeting COL17 is epitope dependent, which is associated with macropinocytosis-mediated endocytosis of immune complexes and finally results in the depletion of COL17 expression in basal keratinocytes.
  • Machiko Nishimura, Wataru Nishie, Yoshinori Shirafuji, Satoru Shinkuma, Ken Natsuga, Hideki Nakamura, Daisuke Sawamura, Keiji Iwatsuki, Hiroshi Shimizu
    HUMAN MOLECULAR GENETICS 25 2 328 - 339 2016年01月 [査読有り][通常論文]
     
    In skin, basal keratinocytes in the epidermis are tightly attached to the underlying dermis by the basement membrane (BM). The correct expression of hemidesmosomal and extracellular matrix (ECM) proteins is essential for BM formation, and the null-expression of one molecule may induce blistering diseases associated with immature BM formation in humans. However, little is known about the significance of post-translational processing of hemidesmosomal or ECM proteins in BM formation. Here we show that the C-terminal cleavage of hemidesmosomal transmembrane collagen XVII (COL17) is essential for correct BM formation. The homozygous p.R1303Q mutation in COL17 induces BM duplication and blistering in humans. Although laminin 332, a major ECM protein, interacts with COL17 around p.R1303, the mutation leaves the binding of both molecules unchanged. Instead, the mutation hampers the physiological C-terminal cleavage of COL17 in the ECM. Consequently, non-cleaved COL17 ectodomain remnants induce the aberrant deposition of laminin 332 in the ECM, which is thought to be the major pathogenesis of the BM duplication that results from this mutation. As an example of impaired cleavage of COL17, this study shows that regulated processing of hemidesmosomal proteins is essential for correct BM organization in skin.
  • Wataru Nishie, Ken Natsuga, Hiroaki Iwata, Kentaro Izumi, Hideyuki Ujiie, Ellen Toyonaga, Hiroo Hata, Hideki Nakamura, Hiroshi Shimizu
    AMERICAN JOURNAL OF PATHOLOGY 185 5 1361 - 1371 2015年05月 [査読有り][通常論文]
     
    Pemphigoid is a common autoimmune blistering disorder in which autoantibodies target transmembrane collagen XVII (COL17), a component of hemidesmosomes in basal keratinocytes. The ectodomain of COL17 can be cleaved from the cell surface within the juxtamembranous extracellular NC16A domain, and, interestingly, certain autoantibodies of pemphigoid patients preferentially react with the shed ectodomain. These findings suggest that COL17 ectodomain shedding generates neoepitopes on the shed form; however, the regulatory mechanism of the shedding in in vivo skin and the pathogenicity of the neoepitope-targeting antibodies still are uncertain. To address these issues, we produced rabbit antibodies specifically reacting with N-terminal cleavage sites of the shed COL17 ectodomain. The antibodies showed that certain amounts of the human COL17 ectodomain are cleaved physiologically at Gln(525) in in vivo skin. In contrast, migrating human keratinocytes cleave COL17 at Leu(524) but not at Gln(525). The passive transfer of antibodies reacting with an N-terminal cleavage site of the mouse COL17 ectodomain into neonatal wild-type mice failed to induce blister formation, even though the antibodies bound to the dermal-epidermal junctions, indicating that cleavage site-specific antibodies have reduced or absent pathogenicity for blister formation. This study shows the ectodomain shedding of COL17 to be a physiological event in in vivo human skin that probably generates nonpathologic epitopes on the cleavage sites.
  • Hideyuki Ujiie, Tetsumasa Sasaoka, Kentaro Izumi, Wataru Nishie, Satoru Shinkuma, Ken Natsuga, Hideki Nakamura, Akihiko Shibaki, Hiroshi Shimizu
    JOURNAL OF IMMUNOLOGY 193 9 4415 - 4428 2014年11月 [査読有り][通常論文]
     
    Complement activation and subsequent recruitment of inflammatory cells at the dermal/epidermal junction are thought to be essential for blister formation in bullous pemphigoid (BP), an autoimmune blistering disease induced by autoantibodies against type XVII collagen (COL17); however, this theory does not fully explain the pathological features of BP. Recently, the involvement of complement-independent pathways has been proposed. To directly address the question of the necessity of the complement activation in blister formation, we generated C3-deficient COL17-humanized mice. First, we show that passive transfer of autoantibodies from BP patients induced blister formation in neonatal C3-deficient COL17-humanized mice without complement activation. By using newly generated human and murine mAbs against the pathogenic noncollagenous 16A domain of COL17 with high (human IgG1, murine IgG2), low (murine IgG1), or no (human IgG4) complement activation abilities, we demonstrate that the deposition of Abs, and not complements, is relevant to the induction of blister formation in neonatal and adult mice. Notably, passive transfer of BP autoantibodies reduced the amount of COL17 in lesional mice skin, as observed in cultured normal human keratinocytes treated with the same Abs. Moreover, the COL17 depletion was associated with a ubiquitin/proteasome pathway. In conclusion, the COL17 depletion induced by BP autoantibodies, and not complement activation, is essential for the blister formation under our experimental system.
  • Ken Natsuga, Wataru Nishie, Ken Arita, Satoru Shinkuma, Hideki Nakamura, Shogo Kubota, Sumihisa Imakado, Masashi Akiyama, Hiroshi Shimizu
    JOURNAL OF INVESTIGATIVE DERMATOLOGY 130 11 2671 - 2674 2010年11月 [査読有り][通常論文]
  • Yasuyuki Fujita, Riichiro Abe, Daisuke Inokuma, Mikako Sasaki, Daichi Hoshina, Ken Natsuga, Wataru Nishie, James R. McMillan, Hideki Nakamura, Tadamichi Shimizu, Masashi Akiyama, Daisuke Sawamura, Hiroshi Shimizu
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 107 32 14345 - 14350 2010年08月 [査読有り][通常論文]
     
    Attempts to treat congenital protein deficiencies using bone marrow-derived cells have been reported. These efforts have been based on the concepts of stem cell plasticity. However, it is considered more difficult to restore structural proteins than to restore secretory enzymes. This study aims to clarify whether bone marrow transplantation (BMT) treatment can rescue epidermolysis bullosa (EB) caused by defects in keratinocyte structural proteins. BMT treatment of adult collagen XVII (Col17) knockout mice induced donor-derived keratinocytes and Col17 expression associated with the recovery of hemidesmosomal structure and better skin manifestations, as well improving the survival rate. Both hematopoietic and mesenchymal stem cells have the potential to produce Col17 in the BMT treatment model. Furthermore, human cord blood CD34(+) cells also differentiated into keratinocytes and expressed human skin component proteins in transplanted immunocompromised (NOD/SCID/gamma(null)(c)) mice. The current conventional BMT techniques have significant potential as a systemic therapeutic approach for the treatment of human EB.
  • Satoru Shinkuma, Masashi Akiyama, Asuka Inoue, Junken Aoki, Ken Natsuga, Toshifumi Nomura, Ken Arita, Riichiro Abe, Kei Ito, Hideki Nakamura, Hideyuki Ujiie, Akihiko Shibaki, Hiraku Suga, Yuichiro Tsunemi, Wataru Nishie, Hiroshi Shimizu
    HUMAN MUTATION 31 5 602 - 610 2010年05月 [査読有り][通常論文]
     
    Autosomal recessive hypotrichosis (ARH) is characterized by sparse hair on the scalp without other abnormalities. Three genes, DSG4, LIPH, and LPAR6 (P2RY5), have been reported to underlie ARH. We performed a mutation search for the three candidate genes in five independent Japanese ARH families and identified two LIPH mutations: c.736T > A (p.Cys246Ser) in all five families, and c.742C > A (p.His248Asn) in four of the five families. Out of 200 unrelated control alleles, we detected c.736T > A in three alleles and c.742C > A in one allele. Haplotype analysis revealed each of the two mutant alleles is derived from a respective founder. These results suggest the LIPH mutations are prevalent founder mutations for ARH in the Japanese population. LIPH encodes PA-PLA(1)alpha (LIPH), a membrane-associated phosphatidic acid-preferring phospholipase A(1)alpha. Two residues, altered by these mutations, are conserved among PA-PLA(1)alpha of diverse species. Cys(246) forms intramolecular disulfide bonds on the lid domain, a crucial structure for substrate recognition, and His(248) is one amino acid of the catalytic triad. Both p.Cys246Ser- and p.His248Asn-PA-PLA(1)alpha mutants showed complete abolition of hydrolytic activity and had no P2Y5 activation ability. These results suggest defective activation of P2Y5 due to reduced 2-acyl lysophosphatidic acid production by the mutant PA-PLA(1)alpha is involved in the pathogenesis of ARH. Hum Mutat 31:602-610, 2010. (C) 2010 Wiley-Liss, Inc.
  • Ken Natsuga, Wataru Nishie, Masashi Akiyama, Hideki Nakamura, Satoru Shinkuma, James R. McMillan, Akari Nagasaki, Cristina Has, Takeshi Ouchi, Akira Ishiko, Yoshiaki Hirako, Katsushi Owaribe, Daisuke Sawamura, Leena Bruckner-Tuderman, Hiroshi Shimizu
    HUMAN MUTATION 31 3 308 - 316 2010年03月 [査読有り][通常論文]
     
    Plectin is a cytoskeletal linker protein that has a dumbbell-like structure with a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC1) cause two distinct autosomal recessive subtypes of epidermolysis bullosa (EB): EB simplex with muscular dystrophy (EBS-MD), and EB simplex with pyloric atresia (EBS-PA). Here, we demonstrate that normal human fibroblasts express two different plectin isoforms including full-length and rodless forms of plectin. We performed detailed analysis of plectin expression patterns in six EBS-MD and three EBS-PA patients. In EBS-PA, expression of all plectin domains was found to be markedly attenuated or completely lost; in EBS-MD, the expression of the N- and C-terminal domains of plectin remained detectable, although the expression of rod domains was absent or markedly reduced. Our data suggest that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBS-MD, and that complete loss or marked attenuation of full-length and rodless plectin expression underlies the more severe EBS-PA phenotype. These results also clearly account for the majority of EBS-MD PLEC1 mutation restriction within the large exon 31 that encodes the plectin rod domain, whereas EBS-PA PLEC1 mutations are generally outside exon 31. Hum Mutat 31:308-316, 2010. (C) 2010 Wiley-Liss, Inc.
  • Gang Wang, Hideyuki Ujiie, Akihiko Shibaki, Wataru Nishie, Yasuki Tateishi, Kazuhiro Kikuchi, Qiang Li, James R. McMillan, Hiroshi Morioka, Daisuke Sawamura, Hideki Nakamura, Hiroshi Shimizu
    AMERICAN JOURNAL OF PATHOLOGY 176 2 914 - 925 2010年02月 [査読有り][通常論文]
     
    Activation of the complement cascade via the classical pathway is required for the development of tissue injury in many autoantibody-mediated diseases. It therefore makes sense to block the pathological action of autoantibodies by preventing complement activation through inhibition of autoantibody binding to the corresponding pathogenic autoantigen using targeted Fab antibody fragments. To achieve this, we use bullous pemphigoid (BP) as an example of a typical autoimmune disease. Recombinant Fabs against the non-collagenous 16th-A domain of type XVII collagen, the main pathogenic epitope for autoantibodies in BP, were generated from antibody repertoires of BP patients by phage display. Two Fabs, Fab-B4 and Fab-19, showed marked ability to inhibit the binding of BP autoantibodies and subsequent complement activation in vitro. In the in vivo experiments using type XVII collagen humanized BP model mice, these Fabs protected mice against BP autoantibody-induced blistering disease. Thus, the blocking of pathogenic epitopes using engineered Fabs appears to demonstrate efficacy and may lead to disease-specific treatments for antibody-mediated autoimmune diseases. (Am J Pathol 2010, 176:914-925; DOI: 10.2353/ajpath.2010.090744)
  • Hideyuki Ujiie, Akihiko Shibaki, Wataru Nishie, Daisuke Sawamura, Gang Wang, Yasuki Tateishi, Qiang Li, Reine Moriuchi, Hongjiang Qiao, Hideki Nakamura, Masashi Akiyama, Hiroshi Shimizu
    JOURNAL OF IMMUNOLOGY 184 4 2166 - 2174 2010年02月 [査読有り][通常論文]
     
    Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humanized (COL17(m-/-,h+)) mice that we recently produced. First, we generated immunodeficient Rag-2(-/-)/COL17-humanized mice by crossing Rag-2(-/-) mice with COL17-humanized mice. Then, splenocytes from wild-type mice that had been immunized by grafting of human COL17-transgenic mouse skin were transferred into Rag-2(-/-)/COL17-humanized mice. The recipient mice continuously produced anti-human COL17 IgG Abs in vivo and developed blisters and erosions corresponding to clinical, histological, and immunopathological features of BP, although eosinophil infiltration, one of the characteristic histological findings observed in BP patients, was not detected in the recipients. Although the depletion of CD8(+) T cells from the immunized splenocytes was found to produce no effects in the recipients, the depletion of CD4(+) T cells as well as CD45R(+) B cells was found to inhibit the production of anti-human COL17 IgG Abs in the recipients, resulting in no apparent clinical phenotype. Furthermore, we demonstrated that cyclosporin A significantly suppressed the production of anti-human COL17 IgG Abs and prevented the development of the BP phenotype in the treated recipients. Although this model in an immunodeficient mouse does not exactly reproduce the induction mechanism of BP in human patients, this unique experimental system targeting humanized pathogenic Ag allows us to investigate ongoing autoimmune responses to human molecules in experimental animal models. The Journal of Immunology, 2010, 184: 2166-2174.
  • Kei Ito, Daisuke Sawamura, Maki Goto, Hideki Nakamura, Wataru Nishie, Kaori Sakai, Ken Natsuga, Satoru Shinkuma, Akihiko Shibaki, Jouni Uitto, Christopher P. Denton, Osamu Nakajima, Masashi Akiyama, Hiroshi Shimizu
    AMERICAN JOURNAL OF PATHOLOGY 175 6 2508 - 2517 2009年12月 [査読有り][通常論文]
     
    Recessive dystrophic epidermolysis bullosa (RDEB) is a severe hereditary bullous disease caused by mutations in COL7A1, which encodes type VU collagen (COL7). coral knockout mice (COL7(m-/-)) exhibit a severe RDEB phenotype and die within a few days after birth. Toward developing novel approaches for treating patients with RDEB, we attempted to rescue COL7(m-/-) mice by introducing human COL7A1 cDNA. we first generated transgenic mice that express human COL7A1 cDNA specifically in either epidermal keratinocytes or dermal fibroblasts. We then performed transgenic rescue experiments by crossing these transgenic mice with COL7(m+/-) heterozygous mice. Surprisingly, human COL7 expressed by keratinocytes or by fibroblasts was able to rescue all of the abnormal phenotypic manifestations of the COL7(m-/-) mice, indicating that fibroblasts as well as keratinocytes are potential targets for RDEB gene therapy. Furthermore, we generated transgenic mice with a premature termination codon expressing truncated COL7 protein and performed the same rescue experiments. Notably, the COL7(m-/-) mice rescued with the human COL7A1 allele were able to survive despite demonstrating clinical manifestations very similar to those of human RDEB, indicating that we were able to generate surviving animal models of RDEB with a mutated human COL7A1 gene. This model has great potential for future research into the pathomechanisms of dystrophic epidermolysis bullosa and the development of gene therapies for patients with dystrophic epidermolysis bullosa. (Am J Pathol 2009,175:2508-2517; DOI: 10.2353/ajpath.2009.090347)
  • Daisuke Sawamura, Maki Goto, Kaori Sakai, Hideki Nakamura, James R. McMillan, Masashi Akiyama, Osamu Shirado, Noritaka Oyama, Masataka Satoh, Fumio Kaneko, Toshiaki Takahashi, Hidehiko Konno, Hiroshi Shimizu
    JOURNAL OF INVESTIGATIVE DERMATOLOGY 127 6 1537 - 1540 2007年06月 [査読有り][通常論文]
  • Wataru Nishie, Daisuke Sawamura, Maki Goto, Kei Ito, Akihiko Shibaki, James R. McMillan, Kaori Sakai, Hideki Nakamura, Edit Olasz, Kim B. Yancey, Masashi Akiyama, Hiroshi Shimizu
    NATURE MEDICINE 13 3 378 - 383 2007年03月 [査読有り][通常論文]
     
    Transmissibility of characteristic lesions to experimental animals may help us understand the pathomechanism of human autoimmune disease. Here we show that human autoimmune disease can be reproduced using genetically engineered model mice. Bullous pemphigoid ( BP) is the most common serious autoimmune blistering skin disease, with a considerable body of indirect evidence indicating that the underlying autoantigen is collagen XVII (COL17). Passive transfer of human BP autoantibodies into mice does not induce skin lesions, probably because of differences between humans and mice in the amino acid sequence of the COL17 pathogenic epitope. We injected human BP autoantibody into Col17-knockout mice rescued by the human ortholog. This resulted in BP-like skin lesions and a human disease phenotype. Humanization of autoantigens is a new approach to the study of human autoimmune diseases.

その他活動・業績

教育活動情報

主要な担当授業

  • 医学研究概論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学研究科
  • 医理工学研究概論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医理工学院
    キーワード : 動物実験、図書館、電子ジャーナル、共同利用施設、RI実験 Animal experiments, library, electric journals, common facilities, radioisotopic experiments
  • 基本医学研究概論
    開講年度 : 2018年
    課程区分 : 修士課程
    開講学部 : 医学院
    キーワード : 動物実験、図書館、電子ジャーナル、共同利用施設、RI実験 Animal experiments, library, electric journals, common facilities, radioisotopic experiments
  • 医学研究概論
    開講年度 : 2018年
    課程区分 : 博士後期課程
    開講学部 : 医学院
    キーワード : 動物実験、図書館、電子ジャーナル、共同利用施設、RI実験 Animal experiments, library, electric journals, common facilities, radioisotopic experiments


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