加齢黄斑変性における網膜色素上皮細胞の危機感知機能の解析

2013 Fiscal Year Annual Research Report

• Project/Area Number: 23592580
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: 羽室 淳爾 京都府立医科大学, 医学(系)研究科(研究院), 教授 (80536095)
• Keywords: 網膜色素上皮組織 / 局所危険感知 / 組織線維化 / 活性化マクロファージ亜集団 / miRNA / 補体活性化抑制因子 / 炎症増悪回路

Research Abstract

マクロファージ（MØ）は加齢黄斑変性(AMD)・ぶどう膜炎など後眼炎症の遷延化、角膜移植後の拒絶反応など広範囲の眼疾患動態を左右する。TNF産生MØ亜集団に選択的アポトーシスを誘導し、AMD病態増悪に係る経路を遮断する方法の樹立を目的とし、インフリキシマブを代替できる汎用性に優れた医療技術開発の基盤の確立を意図する。MØに対し独創的な作用特性を有する新規低分子化合物GRA化合物群の作用解析は24年度に報告した。
本年度は23年度に報告したPPARγ アゴニストとは異なる新規HDAC阻害剤OBP化合物について作用点が網膜色素上皮細胞【RPE】にあること、肝の線維化抑制作用を有するSAGはGRA化合物同様MØに作用することを明らかにした。OBP化合物とGRA化合物もしくはSAGとの併用によるRPE/MØ亜集団間の炎症Vicious 回路の遮断の可能性が示唆された。OBPはTNF＋／－TGFにより誘導される網膜変性、線維化を抑制することを確認した。
補体活性化因子C3, C5, CFB, 補体活性化抑制因子CFH,CD46, CD55, CD59, Clusterin並びにCTRP6, CTRP5などに対するOBPの作用解析も実施した。同時に、ヒト眼球組織を用いてこれら補体抑制因子の後眼部組織における発現様式を免疫組織染色で解析し、正常人とAMD患者由来の眼球での発現分布の差をRPE, ドルーゼン、黄斑部、辺縁部などで比較し、特徴的な差異を見出した。
ヒトRPE株でのこれら補体抑制因子のOBP化合物による発現制御プロファイルも試験管内で解析した。線維化を誘導する、TNF+/-TGFｂ刺激下においてヒトRPE株からの危険感知シグナルとして産生される可溶性miRの分子種を同定するとともに産生される炎症性サイトカインとの対応付けを実施し危険感知応答の新側面を明らかにした。

Research Products

• [Presentation] The role of IL-6 and TNF-alfa in generating the vicious inflammatory cycle between macrophages and retinal pigment epithelium in age-related macular degeneration (2014)
  • Author(s): Jun Yamada, Kenichi Kimura, Atsushi Mukai, Junji Hamuro and Shigeru Kinoshita
  • Organizer: 86th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Orland. FL. U.S.A.
  • Year and Date: 20140506-20140506
• [Presentation] The role of cell to cell interaction through extracellular microvesicles, miRNA and exosome in deregulated functions of RPE and macrophages (2014)
  • Author(s): Atsushi Mukai, Kazuko Asada, Munetoyo Toda, Jun Yamada, Hiroki Hatanaka, Tetusya Yamagishi, Kenji Nagata, Morio Ueno, Junji Hamuro and Shigeru Kinoshita
  • Organizer: 86th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Orland. FL. U.S.A.
  • Year and Date: 20140506-20140506
• [Presentation] The integral analysis of senescence-associated secretory pathway and microRNA secretion of cultured human corneal endothelial cells relating to their functions, cell senescence, and epithelial-mesenchymal transition (2014)
  • Author(s): Morio Ueno, Kazuko Asada, Munetoyo Toda, Michio Hagiya, Naoki Okumura, Noriko Koizumi, Junji Hamuro and Shigeru Kinoshita
  • Organizer: 86th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Orland. FL. U.S.A.
  • Year and Date: 20140506-20140506
• [Presentation] Distinct energy metabolism between cultured mature human corneal endothelial cells and their phenotype transitioned cells (2014)
  • Author(s): Kazuko Asada, Munetoyo Toda, Morio Ueno, Keiko Ujihara, Atsushi Mukai, Michio Hagiya, Naoki Okumura, Noriko Koizumi, Junji Hamuro and Shigeru Kinoshita
  • Organizer: 86th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Orland. FL. U.S.A.
  • Year and Date: 20140506-20140506
• [Presentation] Identification of differentiated mature cultured human corneal endothelial cells and their distinct cell propensity from other immature subpopulations (2014)
  • Author(s): Munetoyo Toda, Morio Ueno, Keiko Ujihara, Kazuko Asada, Takahiro Nakamura, Michio Hagiya, Naoki Okumura, Noriko Koizumi, Junji Hamuro and Shigeru Kinoshita
  • Organizer: 86th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Orland. FL. U.S.A.
  • Year and Date: 20140506-20140506
• [Presentation] レバミピド点眼が細胞内グルタチオンに及ぼす影響及びその作用機序の検討 (2014)
  • Author(s): 堀内稔子, 山田潤, 篠宮克彦, 大石美香子, 横井則彦, 羽室淳爾, 川崎諭, 北澤耕司, 木下茂
  • Organizer: 角膜カンファレンス2014
  • Place of Presentation: 宜野湾
  • Year and Date: 20140131-20140131
• [Presentation] The Role of Cell Senescence, Epithelial-Mesenchymal Transition, and Fibrosis in the Generation of Vicious Inflammatory Cycle Between Macrophages and Retinal Pigment Epithelium (2013)
  • Author(s): Jun Yamada, Hiroki Hatanaka, Kazuko Asada, Kana Nakata, Junji Hamuro and Shigeru Kinoshita
  • Organizer: 85th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Seattle. WS. U.S.A.
  • Year and Date: 20130506-20130506
• [Presentation] Proliferation propensity of cultured human corneal endothelial cells and their plasticity dictated by culture micro-environments (2013)
  • Author(s): Munetoyo Toda, Morio Ueno, Kana Nakata, Kazuko Asada, Michio Hagiya, Naoki Okumura, Noriko Koizumi、Takahiro Nakamura, Junji Hamuro and Shigeru Kinoshita
  • Organizer: 85th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Seattle. WS. U.S.A.
  • Year and Date: 20130506-20130506
• [Presentation] Internal analysis of gene signature and microRNA expression of cultured human corneal endothelial cell in relation to their function, cell senescense, epithelial-mesenchymal transition and fibrosis (2013)
  • Author(s): Kazuko Asada, Munetoyo Toda, Kana Nakata, Michio Hagiya, Morio Ueno, Naoki Okumura, Noriko Koizumi, Takahiro Nakamura, Junji Hamuro and Shigeru Kinoshita
  • Organizer: 85th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Seattle. WS. U.S.A.
  • Year and Date: 20130506-20130506
• [Presentation] 結膜上皮のグルタチオン量判定による眼表面の酸化ストレス評価法 (2013)
  • Author(s): 木村健一,山田潤,羽室淳爾,木下茂
  • Organizer: 第13回日本抗加齢医学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2013-06-28