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: 9251889
• 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/9251889
• 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; TP53 gene; Testing; Therapeutic; Transcriptional Activation; Transcriptional Regulation; Transgenic Mice; United States National Institutes of Health; Vascular Diseases; 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; public health relevance; 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.

 描述（由适用提供）：脉管系统中线粒体增强结构和功能完整性的概念已成为血管功能障碍的新型保护机制。但是，关于负责血管线粒体重塑的精确分子事件存在关键知识差距。我们的初步数据提供了令人信服的证据，表明血管保护单向层流（H-Flow）刺激了线粒体生物发生，融合/裂变动力学，线粒体DNA质量控制机制，并保护内皮细胞免受氧化损伤，细胞敏感性和炎症性活性。在此建议中，我们扩展了此概念和建议，以确定剪切敏感的线粒体重塑的关键分子介体。肿瘤抑制剂p53通过定位到线粒体来调节线粒体功能，从而增强了线粒体蛋白的mtDNA转录调控，我们介绍了p53的线粒体定位的数据，对于剪切应力响应和mtDNA完整性特别重要。长期目标是确定H-Flow在血管壁中维持线粒体稳态的分子机制及其在防止内皮功能障碍和高血压血管功能障碍方面的功能后果。因此，这项拟议研究的目的是确定分子机制，从而剪切应力反应和线粒体生物发生调节内皮功能并检验工作假设，即提高对线粒体功能障碍的耐药性将改善高血压发育。我们的中心假设是诱导剪切应力反应和导致的线粒体重塑将调节内皮氧化剂调节和对血管功能障碍的抗性。为了检验该假设，我们提出了以下特定目的：目标1。研究剪切应力诱导的线粒体重塑的机制可防止内皮功能障碍和高血压。 1A：为了测试H-Flow诱导的内皮线粒体重塑所需的p53的假设。 1b：确定内源性p53在体内的线粒体重塑中的作用。目标2。确定将p53引导到线粒体室的细胞机制和治疗潜力。并抑制mtDNA诱变。 2a：确定p53的线粒体定位对mtDNA稳定性和线粒体生物发生的影响。我们将模拟导向到线粒体（I）外膜，（III）内膜或（III）矩阵的线粒体靶向p53，并量化线粒体生物发生和mtDNA完整性。 2b：研究线粒体p53在mtDNA完整性上的作用和对内皮功能障碍和AngII诱导的高血压的抗性的作用。他提出的研究具有创新性，因为该项目的完成将为血液动力学剪切应力在内皮线粒体网络中的作用增加一个全新的维度，并在线粒体，氧化剂胁迫和血管生物学之间提供界面。