| Project/Area Number |
18K08158
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Jikei University School of Medicine |
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Principal Investigator |
ARAYA JUN 東京慈恵会医科大学, 医学部, 教授 (90468679)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | リソファジー / 慢性閉塞性肺疾患 / 細胞老化 / リソソーム / オートファジー / Galectin3 / TRIM16 / COPD / ガレクチン３ |
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| Outline of Final Research Achievements |
Cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with chronic obstructive pulmonary disease (COPD) pathogenesis. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif proteins (TRIM)16 play a cooperative role in recognizing LMP and inducing lysophagy. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in galectin-3 puncta reflecting lysosomal damage with concomitantly reduced TRIM16 expression levels. HBEC isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Increased LMP, which can be attributed to impaired TRIM16-mediated lysophagy, may be responsible for COPD pathogenesis through the enhancement of cellular senescence.
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| Academic Significance and Societal Importance of the Research Achievements |
老化関連呼吸器疾患であるCOPDは、高齢化社会に伴いその患者数は増加し、社会的にも医療経済的にも、その病態解明と有効な治療法の開発は重要な課題である。
我々はCOPD病態における細胞老化の亢進に、リソソーム傷害の蓄積が関与することを見出した。このリソソーム傷害の機序として、TRIM16という蛋白が関与するリソソーム選択的なオートファジー分解である、リソファジーの機能低下の影響を明らかにした。
リソファジー誘導が、COPD病態の制御に有効である可能性が示されており、今後の治療法開発につながる結果と考えている。
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