Functional implications of fluid shear stress-induced mitochondrial remodeling

流体剪切应力诱导的线粒体重塑的功能意义

• 批准号: 9033945
• 负责人: Joon Young Park
• 金额: $ 42.61万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033945
• 关键词: Address; Adenovirus Vector; Angiotensin II; Antioxidants; Biogenesis; Biology; Blood Vessels; Cardiovascular system; Cell Aging; Cell Survival; Cell physiology; Clinical; Data; Development; Diabetes Mellitus; Dimensions; Disease; Disulfides; Dominant-Negative Mutation; Endothelial Cells; Endothelium; Event; Exercise; Foundations; Genetic Transcription; Goals; Grant; Health; Homeostasis; Hypertension; Inflammatory; Infusion procedures; Knock-out; Knowledge; Liquid substance; Mediator of activation protein; Medicine; Membrane; Metabolic; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Modeling; Molecular; Motion; Mus; Mutagenesis; Organelles; Oxidants; Oxidative Stress; Production; Protein p53; Proteins; Quality Control; Regulation; Reporting; Research Personnel; Resistance; Role; Staging; TP53 gene; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Transgenic Mice; United States National Institutes of Health; Vascular Diseases; Work; biological adaptation to stress; cardiovascular risk factor; endothelial dysfunction; hemodynamics; improved; in vivo; innovation; knowledge base; mitochondrial dysfunction; mtTF1 transcription factor; novel; overexpression; oxidant stress; oxidative damage; preconditioning; prevent; repaired; response; shear stress

 DESCRIPTION (provided by applicant): The concept of enhancing structural and functional integrity of mitochondria in the vasculature has emerged as a novel protective mechanism for vascular dysfunction. However, there is a key knowledge gap with respect to the precise molecular events that are responsible for the vascular mitochondrial remodeling. Our preliminary data provide compelling evidence that vasoprotective unidirectional laminar flow (h-flow) stimulates mitochondrial biogenesis, fusion/fission dynamics, mitochondrial DNA quality control mechanisms and protects the endothelium from oxidative damages, cell senescence and inflammatory activation. In this proposal, we extend this concept and propose to determine the key molecular mediator(s) of the shear sensitive mitochondrial remodeling. The tumor suppressor p53 modulates mitochondrial function by localizing to mitochondria, enhancing mtDNA transcriptional regulation of mitochondrial proteins In this application, we present data that mitochondrial localization of p53 is particularly important for shear stress response and mtDNA integrity. The long-term goal is to determine molecular mechanisms by which h-flow maintains mitochondrial homeostasis in the blood vessel wall and its functional consequence in preventing endothelial dysfunction and hypertensive vascular dysfunction. The objective of this proposed study, therefore, is to determine the molecular mechanisms whereby shear stress response and mitochondrial biogenesis modulate endothelial function and test the working hypothesis that improved resistance to mitochondrial dysfunction will ameliorate the development of hypertension. Our central hypothesis is that induction of the shear stress response and resultant mitochondrial remodeling will modulate endothelial oxidant regulation and resistance to vascular dysfunction. To test this hypothesis we propose the following specific aims: AIM 1. Investigate the mechanism whereby shear stress-induced mitochondrial remodeling prevents endothelial dysfunction and hypertension. 1A: To test the hypothesis that p53 is required for h-flow-induced endothelial mitochondrial remodeling. 1B: To determine the role of endogenous p53 in flow-dependent mitochondrial remodeling in vivo. AIM 2. Determine cellular mechanisms and therapeutic potential of directing p53 to mitochondrial compartments. and suppressing mtDNA mutagenesis. 2A: To determine the effect of differentially targeted mitochondrial localization of p53 on mtDNA stability and mitochondrial biogenesis. We will model mitochondrial targeted p53 directing to mitochondrial (i) outer membrane, (ii) inner membrane or (iii) matrix and quantify mitochondrial biogenesis and mtDNA integrity. 2B: To investigate the role of increased mitochondrial p53 on mtDNA integrity and resistance to endothelial dysfunction and hypertension induced by AngII. T his proposed study is innovative because the completion of this project will add an entirely new dimension to the role of hemodynamic shear stress in the endothelial mitochondrial network and provide an interface between mitochondria, oxidant stress and vascular biology.