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Rab GTPases-mediated mitochondrial clearance in diabetic cardiomyopathy

Rab GTPases 介导的糖尿病心肌病线粒体清除

基本信息

批准号：
9973612
负责人：
Sang Ging Ong
金额：
$ 41.2万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9973612
关键词：
Address Affect Area Autophagocytosis Cardiac Cardiac Myocytes Cardiomyopathies Cardiovascular Diseases Cause of Death Cell Death Cell Line Cell model Cells Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Coronary Arteriosclerosis Cues Data Degradation Pathway Development Diabetes Mellitus Diabetic mouse Disease Ensure Excision Exhibits Exposure to FRAP1 gene Functional disorder Future Generations Genes Genetic Genome Goals Guanosine Triphosphate Phosphohydrolases Heart Heart failure High Fat Diet Human Hyperglycemia Hypertension Impairment Knock-out Knockout Mice Link Lysosomes Mediating Methods Mitochondria Molecular Myocardial dysfunction Non-Insulin-Dependent Diabetes Mellitus Pathogenesis Pathway interactions Patients Pharmacology Phenotype Phosphorylation Predisposition Problem Solving Process Quality Control Reactive Oxygen Species Reagent Reporting Research Research Design Research Personnel Research Proposals Rodent Role Signal Transduction Stress Syndrome System Therapeutic Intervention Transgenic Mice Transgenic Organisms Translating Type 2 diabetic base clinical phenotype db/db mouse diabetic diabetic cardiomyopathy diabetic patient druggable target human model in vivo induced pluripotent stem cell innovation late endosome mitochondrial autophagy mitochondrial dysfunction mortality mouse model novel phosphatidylinositol 3-phosphate prevent rab GTP-Binding Proteins response

项目摘要

PROJECT SUMMARY Diabetic cardiomyopathy is a common yet underestimated cause of heart failure and mortality in patients with diabetes. The underlying basis of this often-fatal syndrome is unknown, although multiple pathways converge on a common denominator - dysfunctional mitochondria. Understanding how damaged mitochondria are removed is critical, as the presence of damaged mitochondria leads to rapid generation of reactive oxygen species which then affect the remaining healthy mitochondria. This leads to wide-spread mitochondrial dysfunction and cell death. Although damaged mitochondria are believed to be degraded by mitochondrial autophagy (a specific form of autophagy), we have recently discovered the existence of a novel endosomal- mediated mitochondrial degradation pathway in cardiomyocytes exposed to hyperglycemia. The suppression of this pathway is potentially linked to increased susceptibility against diabetic cardiomyopathy. This observation was possible due to our ability to generate patient-specific induced pluripotent stem cells (iPSCs) from diabetic patients with (T2DCM) and without (T2D) cardiomyopathy. We found that only T2D cells, but not T2DCM, exhibited increased endosomal-mediated mitochondrial degradation. However, neither the molecular cues regulating this novel pathway, nor the functional significance of this endosomal pathway, is established in cardiomyocytes from a diabetic heart. Thus, the goal of this project is to demonstrate the functional significance of the endosomal-mediated mitochondrial degradation pathway during diabetic cardiomyopathy and to elucidate the underlying mechanisms regulating this pathway. Aim 1 will define the functional role of endosomal-mediated mitochondrial clearance in the diabetic heart by disrupting the function of Rab5 and Rab7, key determinants of the endo-lysosomal system. These studies will employ multiple innovative reagents, including CRISPR-mediated Rab knockout and overactivation iPSC lines and a novel inducible, cardiac-specific Rab7 knockout mouse model, to interrogate the importance of these Rabs in maintaining functional mitochondrial degradation in two distinct diabetic mouse models. Aim 2 will define the role of VPS34/UVRAG in generating phosphatidylinositol 3- phosphate (PI3P) required for endosomal maturation and hence clearance of defective mitochondria. We have supporting data that mTOR is excessively upregulated in selected diabetic patients leading to phosphorylation of UVRAG, impairing its function to form a complex with VPS34 in generating PI3P for proper endosomal maturation and mitochondria degradation. Using both genetic and pharmacological methods, we will demonstrate that maintaining a stable UVRAG/VPS34 complex is a prerequisite for PI3P to mediate conversion of Rab5 into Rab7 for endosomal-mediated mitochondrial degradation. Collectively, these innovative studies will illuminate a novel endosomal-mediated mitochondrial degradation pathway as an important adaptive response in cardiomyocytes when exposed to hyperglycemic stress and pave the way for druggable targets in the future.

项目总结