2021 Fiscal Year Final Research Report

Analysis of extracellular matrix aging in the pathogenesis of TTR amyloidosis

Research Project

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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
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
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.
Free Research Field	アミロイドーシスの病態解析
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。