| Co-Investigator(Kenkyū-buntansha) |
ICHIHASHI Naoki GIFU UNIVERSITY, School of Medicine, Assistant, 医学部附属病院, 助手 (50283304)
ICHIKI Yoshiro GIFU UNIVERSITY, Univ.Hospital, Lecturer, 医学部附属病院, 講師 (30223093)
TAKAGI Hajime GIFU UNIVERSITY, School of Medicine, Associate Professor, 医学部, 助教授 (70226752)
IZUMI Tomoko GIFU UNIVERSITY, School of Medicine, Assistant, 医学部, 助手 (70324291)
ESAKI Chikako GIFU UNIVERSITY, School of Medicine, Assistant, 医学部附属病院, 助手 (70283306)
永井 美貴 (佐藤 美貴) 岐阜大学, 医学部附属病院, 助手 (80324309)
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| Budget Amount *help |
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2002: ¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2001: ¥10,400,000 (Direct Cost: ¥10,400,000)
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| Research Abstract |
Pemphigus (P) is an autoimmune bullous disease caused by disruption of desmosomes due to autoantibodies against desmosomal adhesion molecules, desmoglein 3 (Dsg3) for P vulgaris (PV) or Dsg1 for. P foliaceus (PF). It is yet unknown how blisters are induced after PV-IgG bound to desmogleins. The aim of this study is to elucidate the mechanisms of PV-IgG-induced blistering in terms of outside-in signaling caused by PV-IgG binding and control desmosome adhesion. We have previously showed that PV-IgG causes activation of protein kinase C, mediating the secretion of plasminogen activator (uPA), expression of uPA receptor (uPAR), and phosphorylation of Dsg3 associated with its degradation and dissociation from plakoglobin. In the present study, we revealed the involvement of uPAR in blistering by inhibition experiments using uPAR inhibitors (Gun Exp Dermatol 26: 289-295, 2001), and demonstrated that PV-IgG-binding did not cause steric hindrance of desmosome adhesion (J Invest Dermatol 117: 406, 2001). In addition, we showed that clinical symptoms disappear before the titers of Dsg3-ELISA decreased down to normal range (The 23^<rd> Annual Meeting of Bullous Disease Research Club, 2003). We also presented experimental results on the effects of PV-IgG on the other desmosomal molecules (desmocollins, desmoplakins) (Clin.Exp Dermatol 27 : 684-690, 2002, Arch Dermatol Res 295 : s17-123, 2003), and showed the involvement of acetylcholine receptor function in cell-cell adhesion in keratinocytes (Life Science 72 : 208 1-2085, 2003, Exp Cell Res 2004, in press). Recently, we published new results that PV-IgG and methylprednisoline exhibit reciprocal effects on keratinocytes (J Biol Chem279 : 2132-2146, 2004). Regarding the keratin cytoskeleton and epidermolysis bullosa, we found two new types of mutation and a new clinical type of this diseases caused by a new frame-shift and delayed termination codon mutation (J Dermatol 29 : 136-145, 2002, J Invest Dermatol 121: 482-485, 2003).
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