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: 10538618
• 负责人: JINJU KIM
• 金额: $ 11.03万
• 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/10538618
• 关键词: Adipose tissue; Advisory Committees; Affect; Agreement; Apoptosis; Biological; Catabolism; Cells; Cholesterol; Collagen Type IV; Committee Members; Coupling; Data; Dedications; 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; Institution; 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; Tissues; Training; Triglycerides; Universities; Vocational Guidance; 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.

项目总结/摘要 Alport综合征（AS）是由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）。足细胞是肾小球滤过屏障的关键组成部分， 它们与GBM的相互作用对于保持该屏障的渗透性是至关重要的。我们已经证明 AS实验模型中发生了致病性肾脏脂质蓄积，足细胞脂毒性是导致AS的主要原因。 其他肾小球疾病中足细胞损伤的关键决定因素。我的初步数据显示细胞内 在AS的小鼠模型Col 4a 3 KO小鼠的肾小球中以及在AS的小鼠模型Col 4a 3 KO小鼠的肾小球中，甘油三酯（TG）含量增加。 我从这些小鼠中建立的永生化足细胞（AS足细胞）。然而， AS中哪种脂质积累导致足细胞脂毒性仍有待阐明。 这项研究将探索一种将PLIN 5缺乏与足细胞脂毒性联系起来的新机制。 PLIN 5是一种控制脂解并调节游离脂肪酸（FFA）从脂滴（LD）流向脂滴（LD）的蛋白质。 线粒体通过建立这些细胞器之间的物理接触。根据我的初步数据，我生成了 AS中PLIN 5缺乏导致TG过度脂解和LD-线粒体损失的假说 接触导致FFA积累和线粒体功能障碍。 我提出了以下具体的目标，使用创新的细胞生物学，成像分析，和小鼠模型 方法：（SA 1）研究足细胞PLIN 5在将LD募集到线粒体中的作用。(SA2)定义 PLIN 5缺乏对AS中线粒体功能障碍和肾衰竭的贡献。 我已经制定了一个全面的职业发展计划，并得到了我的导师和合作导师的支持， (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 过渡到一个独立的研究生涯，专注于脂质代谢与 Alport综合征的线粒体功能这个计划包括（1）定期与我的导师，合作伙伴， 导师和咨询委员会，（国家和全球医学和科学学术读者）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， 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， 出版，演示和申请独立研究资金。我和我的导师也同意 制定一个过渡计划，让我和导师的实验室区别开来我的训练将在一个 迈阿密大学米勒医学院无与伦比的学术环境，提供专门的 职业发展计划和所有必要的研究支持和用品通过他的导师，共同导师， 机构核心服务。总的来说，这项研究和职业发展建议是一个产品， 我的野心和能力过渡到一个独立的研究生涯。