Mechanical regulation of vascular metabolism

血管代谢的机械调节

• 批准号: 9192454
• 负责人: David D Wu
• 金额: $ 6.41万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192454
• 关键词: Advisory Committees; Affect; Area; Arterial Fatty Streak; Atherosclerosis; Award; Basic Science; Bioenergetics; Biology; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cell Line; Cell Survival; Cellular Metabolic Process; Chicago; Chronic; Cytoskeletal Modeling; Data; Disease; Doctor of Philosophy; Endothelial Cells; Enzymes; Gene Proteins; Gene Targeting; Genes; Glycolysis; Glycolysis Inhibition; Goals; Health; Human; Hypoxia Inducible Factor; Inflammation; Inflammatory; Inflammatory Response; Iodine; Joints; Laboratories; Lesion; Link; Location; Lysophosphatidic Acid Receptors; Measures; Mechanics; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular and Cellular Biology; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Oxygen; Oxygen Consumption; Pathogenesis; Pathologic; Phase; Physicians; Play; Process; Regulation; Research; Research Project Grants; Role; Scientist; Signal Pathway; Signal Transduction; Site; Techniques; Testing; Therapeutic Intervention; Training; United States; Universities; Up-Regulation; Vascular Permeabilities; Work; angiogenesis; atheroprotective; clinically relevant; human data; insight; knock-down; lysophosphatidic acid; metabolic profile; mortality; post-doctoral training; programs; protein expression; research study; shear stress; small molecule inhibitor; therapeutic target; transcription factor; transcriptome sequencing; transcriptomics; tumor

The proposal outlines a research plan for David Wu, MD PhD, to perform postdoctoral training in the laboratories of Gokhan Mutlu, MD, and Yun Fang, PhD, for two years. The ultimate goal of this research project is to make discoveries in vascular biology that could be useful in promoting human health; another goal is to be- come fluent in the basic techniques in cellular and molecular biology, and ultimately to jump start a research program for the eventual application of a K-level award in vascular biology. During the 2 year mentored period, Dr. Wu will receive additional academic and scientific guidance from the mentors and an advisory committee at the University of Chicago. The overall research goal is to determine the role that shear stress plays on endothelial cell (EC) metabolism, which plays a fundamental role in endothelial activation. Endothelial activation is the process by which ECs have reduced barrier function and increased inflammation. That endothelial activation occurs with a significant upregulation of glycolysis is a recently discovered phenomenon. That low shear stress generated by “atheroprone” blood flow (as opposed to high shear stress during normal, “atheroprotective” blood flow) is important in determining endothelial activation is also well-described. However, how changes in shear stress produce changes in the metabolism of ECs is unknown. Dr. Wu now has confirmatory data that human aortic endothelial cells (HAECs) exposed to atheroprone flow upregulate key enzymes in glycolysis, angiogenesis, and inflammation. Dr. Wu also has preliminary data that suggests HAECs are unable to use their mitochondria to generate energy under atheroprone flow. Excitingly, he recently found that atheroprone flow led to normoxic stabilization of transcription factor hypoxia inducible factor-1α (HIF-1α), which is known to upregulate glycolysis in many other contexts. This is counterintuitive, as HIF-1α activity is thought to be suppressed in high oxygen tension settings, such as in arterial blood flow. Furthermore, Dr. Wu found that lysophosphatidic acid (LPA) signaling, increased in atheroprone flow (and working through RhoA and Rac1, small GTPases which modulate cytoskeletal organization), and also known to be a key mediator of atherosclerosis, also induces HIF-1α. Collectively, these results led to his central hypothesis: atheroprone flow-mediated modulation of LPA signaling through RhoA or Rac1 leads to metabolic changes in a HIF-1α dependent manner. Aim 1 will test the hypothesis that HIF-1α stabilization is required for upregulation of glycolysis, mitochondrial insufficiency, and EC activation under atheroprone flow. Aim 2 will test the hypothesis that atheroprone flow stabilizes HIF-1α through LPA signaling via RhoA and Rac1. The goal is to achieve a mechanistic understanding of shear-stress related changes in metabolism. Endothelial activation occurs naturally in atheroprone flow states (near valves and arterial branch points) – this results in chronic inflammation and ultimately atherosclerosis, a leading cause of morbidity and mortality in the United States. Thus, there is a significant need to better understand how shear stress induces metabolic changes and hence EC activation.

该提案概述了医学博士 David Wu 的一项研究计划，即在医学博士 Gokhan Mutlu 和方云博士的实验室进行为期两年的博士后培训。该研究项目的最终目标是在血管生物学方面取得发现。这可能有助于促进人类健康；另一个目标是熟练掌握细胞和分子生物学的基本技术，并最终启动一项研究计划，最终将 K 级奖项应用于血管生物学。 2在一年的指导期间，吴博士将接受来自芝加哥大学导师和咨询委员会的额外学术和科学指导，总体研究目标是确定剪切应力对内皮细胞（EC）代谢的作用。内皮激活是内皮细胞降低屏障功能和增加炎症的过程，这是最近发现的一种现象，即糖酵解显着上调。 “动脉粥样硬化”血流（与正常“动脉粥样硬化”血流期间的高剪切应力相反）对于确定内皮激活也很重要，但剪切应力的变化如何引起 EC 代谢的变化尚不清楚。吴博士现在已经得到了证实的数据，即暴露于动脉粥样硬化流的人主动脉内皮细胞（HAEC）会上调糖酵解、血管生成和炎症中的关键酶。吴博士也有初步的数据。令人兴奋的是，他最近发现动脉粥样硬化流导致转录因子缺氧诱导因子-1α (HIF-1α) 的常氧稳定，众所周知，HIF-1α 会上调糖酵解。这是违反直觉的，因为 HIF-1α 活性被认为在高氧张力环境（例如动脉血流）中受到抑制。此外，Wu 博士发现，溶血磷脂酸 (LPA) 信号在动脉粥样硬化血流中增加（并通过 RhoA 和 Rac1（调节细胞骨架组织的小 GTP 酶发挥作用），也被认为是动脉粥样硬化的关键介质，也会诱导 HIF-1α总的来说，这些结果引出了他的中心假设：通过 RhoA 或 Rac1 的动脉粥样硬化易发性血流介导的 LPA 信号调节，导致代谢变化目标 1 将验证 HIF-1α 稳定是动脉粥样硬化流下糖酵解、线粒体功能不全和 EC 激活所必需的假设，目标 2 将验证动脉粥样硬化流通过 LPA 稳定 HIF-1α 的假设。通过 RhoA 和 Rac1 信号传导的目标是实现对代谢中自然发生的剪切应力相关变化的机制理解。动脉粥样硬化流动状态（瓣膜和动脉分支点附近）——这会导致慢性炎症并最终导致动脉粥样硬化，这是美国发病和死亡的主要原因。因此EC被激活。