Role of Atp6ap2 in renal proximal tubule lipotoxicity

Atp6ap2 在肾近曲小管脂毒性中的作用

• 批准号: 10591837
• 负责人: Silas A Culver
• 金额: $ 16.67万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591837
• 关键词: Albumins; Animals; Area; Award; Basic Science; Binding; Biomedical Research; Cell Death; Cells; Chronic Kidney Failure; Complement; Complex; Coupled; Data; Development; Development Plans; Diabetes Mellitus; Endocrinology; Endocytosis; Environment; Epithelial Cells; Excretory function; FRAP1 gene; Fatty Acids; Filtration; Foundations; Functional disorder; Future; Genus Hippocampus; Goals; High Fat Diet; High Pressure Liquid Chromatography; In Vitro; Injury to Kidney; Intracellular Accumulation of Lipids; Investigation; Kidney; Kidney Diseases; Knock-out; Knockout Mice; LDL-Receptor Related Protein 2; Laboratories; Lipids; Magnetic Resonance Imaging; Mass Spectrum Analysis; Mediating; Mentors; Mentorship; Methods; Microscopy; Modification; Mus; Nephrons; Obesity; Obesity Epidemic; Obesity associated kidney disease; Oxidative Stress; Pathology; Peripheral; Physicians; Predisposition; Prevalence; Prevention; Prevention strategy; Process; Proton-Translocating ATPases; Proximal Kidney Tubules; Research; Research Training; Risk Factors; Role; Scanning; Science; Scientist; Signal Transduction; Small Interfering RNA; Techniques; Testing; Time; Tissues; Training; Transgenic Mice; Translational Research; Universities; Virginia; Writing; absorption; career; career development; cell type; diabetic; diet-induced obesity; endoplasmic reticulum stress; experience; fatty acid oxidation; in vitro Model; in vivo; interest; intravital imaging; intrinsic factor-cobalamin receptor; kidney cell; kidney cortex; kidney dysfunction; knock-down; lipid metabolism; lipidomics; microscopic imaging; mitochondrial dysfunction; mouse model; new therapeutic target; novel strategies; novel therapeutic intervention; obesity management; obesity treatment; oxidation; pharmacologic; prevent; receptor mediated endocytosis; research facility; uptake; urinary; vacuolar H+-ATPase

Project Summary The rising rates of obesity worldwide contribute directly to an increased prevalence of chronic kidney disease. With current methods for mitigating obesity related kidney injury incompletely effective, novel approaches to this problem are needed. In renal lipotoxicity, toxic lipid metabolites accumulate in certain kidney cell types, including proximal tubule cells. This has recently been identified as an important mechanism behind obesity related kidney disease but is also not well understood. In obesity, greater proximal tubule uptake of lipid occurs through increased luminal endocytosis of fatty acid bound to albumin, facilitated by interaction of the vacuolar H+ -ATPase and mTOR with the megalin/cubulin complex. At the same time, decreased activation of renal AMPK in obesity leads to decreased fatty acid oxidation through inactivation of PGC-1α, and CPT1A, further resulting in intracellular lipid accumulation in the proximal tubule. ATP6AP2 is an integral component of the vacuolar H+ -ATPase and has also been shown to have a role in intracellular energy signaling including inhibition of AMPK and PGC-1α as well as activation of mTOR in diabetes. Renal cortical ATP6AP2 expression increases in obesity but its role in lipotoxicity is unknown. Mice with nephron specific ATP6AP2 knockout during obesity have increased urinary excretion of albumin and fatty acid, reduced proximal tubule lipid content during diet induced obesity, decreased endoplasmic reticulum stress, a marker of lipotoxicity, and altered intrarenal lipid profile. This proposal will test the hypothesis that in obesity ATP6AP2 promotes proximal tubule lipotoxicity through endocytosis of albumin bound fatty acid as well as reduced intracellular fatty acid oxidation. Aim 1 proposes that ATP6AP2 increases fatty acid endocytosis through the H+ -ATPase/mTOR/megalin/cubulin. Aim 2 will test the hypothesis that ATP6AP2 reduces fatty acid oxidation through AMPK/PGC-1α/CPT1A.. This project will also greatly facilitate my career development toward the goal of becoming a fully independent physician scientist performing basic and translational research. The career development plan described in this application will include formal training in lipid science and lipidomics, the use of transgenic mouse models, microscopy, and scientific writing, as well as mentorship by leaders in endocrinology and lipid science including my mentors Drs. Helmy Siragy and Thurl Harris. This will take place at the University of Virginia, an excellent research training environment with state-of-the art research facilities and core laboratories as well as a superb academic environment for early career scientists. Data generated by the proposed studies will establish the basis for an independent research career, distinct from my mentors.

项目摘要 世界范围内肥胖率的上升直接导致慢性肾脏疾病患病率的增加。 疾病。目前减轻肥胖相关肾损伤的方法不完全有效，新颖 解决这个问题的方法是必要的。在肾脏脂毒性中，有毒的脂质代谢物在某些 肾细胞类型，包括近端小管细胞。最近，这被确认为一种重要的机制 肥胖与肾脏疾病有关，但也不是很清楚。 肥胖患者，近端小管对脂肪的摄取增加是通过增加脂肪的管腔内吞作用来实现的。 与白蛋白结合的酸，通过液泡H+-ATPase和mTOR与白蛋白的相互作用促进 巨蛋白/立方体蛋白复合体。同时，肥胖症患者肾脏AMPK活性降低导致其活性下降 通过pGC-1α和CPT1a失活的脂肪酸氧化，进一步导致细胞内脂质 积聚在近端小管。ATP6AP2是液泡H+-ATPase的一个组成部分，它具有 也被证明在细胞内能量信号转导中起作用，包括抑制AMPK和PGC-1αAS 糖尿病时mTOR的激活。肾皮质ATP6AP2在肥胖中的表达增加，但在肥胖中的作用 脂毒性尚不清楚。肥胖期间肾单位特异性ATP6AP2基因敲除的小鼠尿量增加 在饮食诱导的肥胖过程中，白蛋白和脂肪酸的排泄，近端小管脂肪含量的减少， 降低内质网应激(脂毒性的标志)，并改变肾内脂类分布。这 该提案将检验肥胖患者ATP6AP2通过以下途径促进近端小管脂肪毒性的假设 白蛋白结合脂肪酸的内吞作用以及减少细胞内脂肪酸氧化。目标1建议 ATP6AP2通过H+-ATPase/mTOR/megalin/cuBulin增加脂肪酸内吞作用。目标2将 验证ATP6AP2通过AMPK/PGC-1α/CPT1a途径减少脂肪酸氧化的假说。 这个项目也将极大地促进我的职业发展，朝着成为一名完全 从事基础研究和翻译研究的独立内科科学家。职业发展计划 在这一应用中所描述的将包括在脂类科学和脂类组学方面的正式培训，转基因的使用 小鼠模型、显微镜和科学写作，以及内分泌学和脂类领域领袖的指导 科学，包括我的导师赫尔米·西拉吉博士和瑟尔·哈里斯博士。该活动将在芝加哥大学举行。 弗吉尼亚州，拥有最先进的研究设施和核心技术的优秀研究培训环境 实验室以及为早期职业科学家提供的一流学术环境。生成的数据 提议的研究将为独立的研究生涯奠定基础，这与我的导师不同。