Pathophysiological role of organelle contact site in tubular homeostasis
| Project/Area Number |
21K19439
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 52:General internal medicine and related fields
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Inagi Reiko 東京大学, 医学部附属病院, 特任教授 (50232509)
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| Co-Investigator(Kenkyū-buntansha) |
平川 陽亮 東京大学, 医学部附属病院, 助教 (10780736)
長谷川 頌 東京大学, 医学部附属病院, 特任助教 (30892658)
南学 正臣 東京大学, 医学部附属病院, 教授 (90311620)
西 裕志 東京大学, 医学部附属病院, 准教授 (90784174)
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| Project Period (FY) |
2021-07-09 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
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| Keywords | オルガネラストレス / 尿細管上皮細胞 / 尿細管障害 / オルガネラコンタクトサイト / 代謝リプログラミング / 脂肪毒性 / オルガネラ間相互作用 / リゾリン脂質 / 尿細管間質障害 / 慢性腎臓病 |
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| Outline of Research at the Start |
慢性腎臓病を含む生活習慣病の新薬には、オルガネラ機能を改善し臓器保護効果を示すものが散見される。このことからオルガネラ相互作用を基軸にオルガネラ研究を更に発展させることは、新たな細胞機能維持機構やその破綻による病因論の解明、ひいては革新的な創薬標的分子の同定に繋がる。
本研究は、オルガネラ研究の中でも新研究領域であるオルガネラコンタクトサイト、特にmitochondria-associated membrane (MAM) に着目し、それらの尿細管における構造や生理活性、尿細管障害（代謝変動、炎症・線維化）との関連性などを分子レベルで解明し、腎臓病学に新たな展開をもたらすことを目指す。
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| Outline of Final Research Achievements |
To assess pathophysiological role of organelle contact site in tubular homeostasis, plasma and urine samplers from diabetic kidney disease (DKD) patients and DKD model rats were examined by metabolomic and lipidomic analyses.
We identified Lysophosphatidylcholine（LPC) as a biomarker of fast decline in kidney function in DKD.
LPC accumulated in the proximal tubular cells decreased mitochondria-associated membrane (MAM) formation, in turn leading to organelle stress (endoplasmic reticulum and mitochondrial dysfunction) in association of metabolic alteration. Further, MAM-related gene expression is altered in tubular damage and linked to tubular phenotypic changes, such as tubular cell death and inflammation.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、小胞体、ミトコンドリアなどのオルガネラ研究を発展させ、オルガネラコンタクトサイト、特にmitochondria-associated membrane (MAM)に着目し、それらの腎臓における分子生物学的活性、腎臓細胞障害(代謝変動、炎症・線維化)との関連性などを解明することを目標とした。
一連の腎臓におけるオルガネラ研究、特にオルガネラコンタクトサイト研究の成果は、尿細管細胞恒常性、あるいは病態形成メカニズムを新たな視点から理解し、革新的な腎臓病病因論の確立に繋がることが期待される。
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Report
(3 results)
Research Products
(43 results)
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[Journal Article] International Society of Nephrology first consensus guidance for preclinical animal studies in translational nephrology2023
Author(s)
Nangaku M, Kitching AR, Boor P, Fornoni A, Floege J, Coates PT, Himmelfarb J, Lennon R, Anders HJ, Humphreys BD, Caskey FJ, Fogo AB; TRANSFORM group.
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Journal Title
Kidney International
Volume: S0085-2538(23)00174-6
Issue: 1
Pages: 36-45
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Early Identification of CKD-A Scoping Review of the Global Populations2022
Author(s)
Okpechi IG, Caskey FJ, Gaipov A, Tannor EK, Noubiap JJ, Effa E, Ekrikpo UE, Hamonic LN, Ashuntantang G, Bello AK, Donner JA, Figueiredo AE, Inagi R, Madero M, Malik C, Moorthy M, Pecoits-Filho R, Tesar V, Levin A, Jha V.
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Journal Title
Kidney International Reports
Volume: 7
Issue: 6
Pages: 1341-1353
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Bone marrow stromal cell antigen-1 (CD157) regulated by sphingosine kinase 2 mediates kidney fibrosis2022
Author(s)
Inoue T, Nakamura Y, Tanaka S, Kohro T, Li LX, Huang L, Yao J, Kawamura S, Inoue R, Nishi H, Fukaya D, Uni R, Hasegawa S, Inagi R, Umene R, Wu CH, Ye H, Bajwa A, Rosin DL, Ishihara K, Nangaku M, Wada Y, Okusa MD
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Journal Title
Frontiers in Medicine
Volume: 9
Pages: 993698-993698
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Activation of Sympathetic Signaling in Macrophages Blocks Systemic Inflammation and Protects against Renal Ischemia-Reperfusion Injury2021
Author(s)
Hasegawa S, Inoue T, Nakamura Y, Fukaya D, Uni R, Wu CH, Fujii R, Peerapanyasut W, Taguchi A, Kohro T, Yamada S, Katagiri M, Ko T, Nomura S, Nakanishi Ozeki A, Susaki EA, Ueda HR, Akimitsu N, Wada Y, Komuro I, Nangaku M, Inagi R.
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Journal Title
J Am Soc Nephrol.
Volume: -
Issue: 7
Pages: 1599-1615
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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