Analysis of extracellular matrix aging in the pathogenesis of TTR amyloidosis

• Project/Area Number: 19K07869
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52010:General internal medicine-related
• Research Institution: Kumamoto University
• Principal Investigator: Misumi Yohei 熊本大学, 病院, 講師 (80625781)
• Co-Investigator(Kenkyū-buntansha): 井上 泰輝 熊本大学, 大学院生命科学研究部(医), 特定研究員 (00806408) ; 増田 曜章 熊本大学, 病院, 助教 (50464459) ; 植田 光晴 熊本大学, 病院, 教授 (60452885) ; 山下 太郎 熊本大学, 病院, 非常勤診療医師 (90381003)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: アミロイド / 細胞外マトリックス / 線維芽細胞 / トランスサイレチン / 細胞老化 / 組織老化 / 老化

Outline of Research at the Start

本研究は、細胞外マトリックス（ECM）の老化とアミロイド線維形成の関連という根源的かつ新たな視点から、［1］ECMを維持する線維芽細胞の細胞老化、[2] ECMの主要構成分子の終末糖化産物（Advanced glycation end products: AGEs）化による老化架橋形成、[3] 本症のモデルマウス皮膚の光老化がアミロイド線維形成、分解にどのような影響を与えるかを詳細に解析する。

Outline of Final Research Achievements

Extracellular matrix is an extremely important tissue environment that on the pathogenesis of amyloidosis. In order to analyze changes in TTR degradation-removing ability and amyloid formation-inhibiting ability due to cell aging of fibroblasts, we performed analysis in a three-dimensional culture system using collagen gel and fibroblast lines that imitated ECM in vivo. Large amount of amyloid fibrils, aggregated TTR, and fragmented TTR were deposited inside fibroblasts, and co-localization of amyloid and lysosomal markers was observed. Decreased lysosomal markers and marked aging-related changes in intracellular structure were observed in fibroblasts with a large amount of amyloid uptake.

Academic Significance and Societal Importance of the Research Achievements

トランスサイレチンアミロイドーシスにおいてアミロイド線維形成と除去がダイナミックに起こっている細胞外マトリックスの主要な構成細胞である線維芽細胞は 非線維性トランスサイレチン凝集体を細胞内に取り込み分解し保護的に働くが、既にアミロイド線維となったトランスサイレチンは分解し難く、細胞内蓄積および細胞老化および細胞障害を誘導することか示唆され、アミロイドーシスの病態解明に有用な知見が得られた。

Research Products

• [Journal Article] Current Management and Therapeutic Strategies for Cerebral Amyloid Angiopathy (2021)
  • Author(s): Yasuteru Inoue, Yukio Ando, Yohei Misumi, Mitsuharu Ueda
  • Journal Title: Int J Mol Sci Volume: 22 Issue: 8 Pages: 3869-3869
  • DOI: 10.3390/ijms22083869
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Metformin attenuates vascular pathology by increasing expression of insulin-degrading enzyme in a mixed model of cerebral amyloid angiopathy and type 2 diabetes mellitus (2021)
  • Author(s): Inoue Yasuteru、Masuda Teruaki、Misumi Yohei、Ando Yukio、Ueda Mitsuharu
  • Journal Title: Neuroscience Letters Volume: 762 Pages: 136136-136136
  • DOI: 10.1016/j.neulet.2021.136136
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Glavonoid, a possible supplement for prevention of ATTR amyloidosis (2021)
  • Author(s): Matsushita Hiroaki、Isoguchi Aito、Okada Masamitsu、Masuda Teruaki、Misumi Yohei、Tsutsui Chiharu、Yamaguchi Narumi、Ichiki Yuko、Sawashita Jinko、Ueda Mitsuharu、Mizuguchi Mineyuki、Ando Yukio
  • Journal Title: Heliyon Volume: 7 Issue: 10 Pages: e08101-e08101
  • DOI: 10.1016/j.heliyon.2021.e08101
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ドミノ肝移植の二次レシピエントに生じた ATTR アミロイドーシスの長期臨床経過の解析 (2021)
  • Author(s): 三隅洋平、増田曜章、野村隼也、岡田匡充、植田光晴
  • Organizer: 日本神経学会学術集会