Role of Atp6ap2 in renal proximal tubule lipotoxicity

Atp6ap2 在肾近曲小管脂毒性中的作用

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要全球肥胖的速度上升直接导致慢性肾脏的患病率提高疾病。使用当前缓解对象性相关肾脏损伤的方法不完全有效，新颖需要解决这个问题。在肾脂毒性中，有毒脂质代谢产物在某些肾细胞类型，包括近端小管细胞。最近，这被确定为重要的机制与肥胖有关的肾脏疾病背后，但也没有得到充分了解。在对象性中，通过增加的脂肪内吞作用，脂质的近端近端脂质摄取发生与专辑结合的酸，通过吸尘器H+ -ATPase和MTOR与MTOR的相互作用促进 Megalin/Cubulin复合物。同时，肥胖症中肾脏AMPK的激活减少导致降低通过PGC-1α和CPT1A灭活脂肪酸氧化，进一步导致细胞内脂质在近端管中积聚。 ATP6AP2是真空h+ -ATPase的组成部分，有还显示在细胞内能信号传导中起作用，包括抑制AMPK和PGC-1α作为以及糖尿病中MTOR的激活。肾皮质ATP6AP2表达在肥胖症中增加，但其在脂肪毒性尚不清楚。肥胖期间使用肾单位特异性ATP6AP2敲除的小鼠增加了尿白蛋白和脂肪酸的排泄，饮食诱导肥胖期间近端细胞脂质含量减少，内质网应激降低，脂肪毒性的标记和肾内脂质谱的改变。这提案将检验以下假设：肥胖症中ATP6AP2在白蛋白结合脂肪酸以及减少细胞内脂肪酸氧化的内吞作用。目标1提案 ATP6AP2通过H+ -ATPase/MTOR/MEGALIN/CUBIN增加脂肪酸内吞作用。 AIM 2意志测试ATP6AP2通过AMPK/PGC-1α/CPT1A降低脂肪酸氧化的假设。该项目还将极大地支持我的职业发展，以完全成为一个完全独立的物理科学家进行基础和翻译研究。职业发展计划本应用程序中描述的将包括脂质科学和脂质组学的正式培训，转基因的使用鼠标模型，显微镜和科学写作以及内分泌学领域和脂质领导者的指导包括我的导师博士在内的科学。 Helmy Siragy和Thurl Harris。这将在大学弗吉尼亚州，具有最先进的研究设施和核心的出色研究培训环境实验室以及早期职业科学家的出色学术环境。由拟议的研究将建立与我的导师不同的独立研究职业的基础。