The role of PLIN5 deficiency in podocyte lipotoxicity and progression of Alport Syndrome

PLIN5 缺陷在足细胞脂毒性和 Alport 综合征进展中的作用

• 批准号: 10371400
• 负责人: JINJU KIM
• 金额: $ 11.18万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371400
• 关键词: Adipose tissue; Advisory Committees; Affect; Apoptosis; Biological; Catabolism; Cells; Cholesterol; Collagen Type IV; Committee Members; Coupling; Data; Development Plans; Diabetes Mellitus; Dialysis procedure; Ear; Ensure; Environment; Experimental Models; Eye; Failure; Family; Family member; Fellowship; Filtration; Funding; Goals; Growth; Health; Hereditary Disease; Hereditary nephritis; Human; Hypertriglyceridemia; Image; Injury; Kidney; Kidney Diseases; Kidney Failure; Knockout Mice; Laboratories; Learning; Life; Link; Lipase; Lipids; Lipolysis; Liver; Mediating; Medicine; Membrane Potentials; Mentors; Metabolic; Metabolism; Methodology; Microscopy; Mitochondria; Mus; Names; Nonesterified Fatty Acids; Organelles; Pathogenicity; Patients; Permeability; Pharmaceutical Preparations; Physiological; Play; Program Development; Proteins; Publications; Reader; Regulation; Renal glomerular disease; Research; Research Proposals; Research Support; Respiration; Respiratory physiology; Role; Science; Services; Testing; Training; Triglycerides; Universities; Vocational Guidance; base; career; career development; cytotoxicity; defined contribution; disease-causing mutation; ezetimibe; fatty acid metabolism; glomerular basement membrane; glomerular filtration; improved; in vivo; innovation; lipid metabolism; lipidomics; medical schools; meetings; member; mitochondrial dysfunction; mitochondrial membrane; mouse model; novel; obese patients; overexpression; perilipin; perilipin A; podocyte; prevent; protein expression; recruit; research and development; restoration; skills; success; uptake

PROJECT SUMMARY/ABSTRACT Alport Syndrome (AS) is a hereditary disease caused by mutations in collagen type IV, a main component of the glomerular basement membrane (GBM). Podocytes are key components of the glomerular filtration barrier, and their interaction with the GBM is crucial to maintain the permeability of this barrier. We have demonstrated that pathogenic renal lipid accumulation occurs in an experimental model of AS and that podocyte lipotoxicity is the key determinant of podocyte injury in other glomerular disease. My preliminary data show that the intracellular triglyceride (TG) content is increased in glomeruli of Col4a3 KO mice, a mouse model for AS as well as in immortalized podocytes which I established from these mice (AS podocytes). Yet, the detailed mechanism by which lipid accumulation contributes to podocyte lipotoxicity in AS remains to be elucidated. The proposed research will explore a novel mechanism linking PLIN5 deficiency to podocyte lipotoxicity. PLIN5 is a protein controls lipolysis and regulates free fatty acid (FFA) flux from lipid droplets (LDs) to mitochondrial by establishing physical contact between these organelles. From my preliminary data, I generated the hypothesis that PLIN5 deficiency in AS causes excessive TG lipolysis and loss of LD-mitochondrial contacts resulting in FFA accumulation and mitochondrial dysfunction. I propose the following specific aims using innovative cell biological, imaging analysis, and mouse model approaches: (SA1) investigate the role of podocyte PLIN5 in recruiting LDs to mitochondria. (SA2) Define the contribution of PLIN5 deficiency to mitochondrial dysfunction and renal failure in AS. I have created a comprehensive career development plan supported by my mentor and co-mentors to (1) ensure my progress and success in carrying out this research proposal and (2) to facilitate my transition to an independent research career focused on lipid metabolism in association with mitochondrial function in Alport Syndrome. This plan includes (1) regular meetings with my mentor, co- mentors, and advisory committee, (national and global academic readers in medicine and science) to provide research and career guidance, (2) research and career development seminars, learning new methodologies of microscopy, mitochondrial function, and lipidomics, and (3) activities for career growth including mentoring, publication, presentation, and application for independent research funding. My mentor and I have also agreed upon a transition plan to distinguish myself from my mentor’s laboratory. My training will be carried out in an unparalleled academic environment at University of Miami, Miller School of Medicine, which provides dedicated career development programs and all necessary research support and supplies through his mentor, co-mentors, and institutional core services. Collectively, this research and career development proposal is a product of my ambition and capacity to transition to an independent research career.

项目概要/摘要 阿尔波特综合症 (AS) 是一种由 IV 型胶原蛋白突变引起的遗传性疾病，IV 型胶原蛋白是胶原蛋白的主要成分。 肾小球基底膜 (GBM) 是肾小球滤过屏障的关键组成部分， 它们与 GBM 的相互作用对于维持这一屏障的渗透性至关重要。 肾 AS 实验模型中发生致病性脂质积累，足细胞脂毒性是 我的初步数据表明，细胞内足细胞损伤是其他肾小球疾病的关键决定因素。 Col4a3 KO 小鼠（AS 小鼠模型）的肾小球中甘油三酯 (TG) 含量增加 我从这些小鼠中建立了永生化足细胞（AS足细胞），但详细机制尚不清楚。 哪些脂质积累导致 AS 足细胞脂毒性仍有待阐明。 拟议的研究将探索一种将 PLIN5 缺陷与足细胞脂毒性联系起来的新机制。 PLIN5 是一种蛋白质，可控制脂肪分解并调节从脂滴 (LD) 到脂肪细胞的游离脂肪酸 (FFA) 通量。 根据我的初步数据，我生成了通过在这些细胞器之间建立物理接触来实现线粒体。 AS 中 PLIN5 缺陷导致过度 TG 脂解和 LD 线粒体损失的假设 接触导致 FFA 积累和线粒体功能障碍。 我利用创新的细胞生物学、成像分析和小鼠模型提出以下具体目标 方法：（SA1）研究足细胞 PLIN5 在将 LD 招募到线粒体中的作用（SA2）定义 PLIN5 缺陷对 AS 线粒体功能障碍和肾功能衰竭的影响。 我在导师和共同导师的支持下制定了全面的职业发展计划 (1) 确保我在执行这项研究计划方面取得进展和成功，以及 (2) 促进我 过渡到专注于与脂质代谢相关的独立研究生涯 阿尔波特综合症中的线粒体功能 该计划包括 (1) 与我的导师、同事定期会面。 导师和咨询委员会（医学和科学领域的国内和全球学术读者）提供 研究和职业指导，（2）研究和职业发展研讨会，学习新的方法论 显微镜、线粒体功能和脂质组学，以及 (3) 职业发展活动，包括指导、 我和我的导师也同意发表、演示和申请独立研究经费。 为了使自己与导师的实验室区分开来，我制定了一个过渡计划。我的培训将在一个实验室中进行。 迈阿密大学米勒医学院无与伦比的学术环境，提供专门的 职业发展计划以及通过他的导师、共同导师提供的所有必要的研究支持和用品， 总的来说，这项研究和职业发展提案是以下各项的产物。 我过渡到独立研究职业的雄心和能力。