Regulation of vascular metabolism in acute lung injury

急性肺损伤中血管代谢的调节

• 批准号: 10308833
• 负责人: David D Wu
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308833
• 关键词: Academic advising; Actins; Acute Lung Injury; Adult Respiratory Distress Syndrome; Advisory Committees; Aldolase A; Atherosclerosis; Award; Biomedical Engineering; Biomedical Research; Biophysics; Blood Vessels; Cells; Chicago; Clinical; Complex; Coupled; Cytoskeleton; Data; Development Plans; Disease; Doctor of Philosophy; Down-Regulation; Electron Transport; Electrons; Endothelial Cells; Endothelium; Endotoxins; Energy-Generating Resources; Enzymes; Equilibrium; Fellowship; Fluorescence Microscopy; Functional disorder; Funding; Generations; Genetic Transcription; Glycolysis; Goals; In Vitro; Inflammation; Inflammatory; Injury; Knowledge; Laboratories; Lead; Link; Lung; Measures; Mechanics; Mediating; Mentors; Metabolic; Metabolic Diseases; Metabolism; Microscopy; Mitochondria; Molecular Analysis; Molecular Biology; Monomeric GTP-Binding Proteins; Mus; Names; Optics; Oxidases; Oxidative Phosphorylation; Pathogenesis; Pathologic; Pathway interactions; Permeability; Phase; Phenotype; Physicians; Play; Positioning Attribute; Postdoctoral Fellow; Prevention; Production; Reactive Oxygen Species; Regulation; Research; Research Proposals; Role; Scientist; Sepsis; System; Testing; Training; Transgenic Mice; United States National Institutes of Health; Universities; Up-Regulation; Vascular Diseases; Vascular Permeabilities; Work; alternative oxidase; career; career development; design; electron energy; endothelial dysfunction; hemodynamics; in vivo; lung injury; mouse model; new therapeutic target; overexpression; post-doctoral training; prevent; programs; research and development; sensor; shear stress; skills; small molecule; therapeutic target; transport inhibitor; vascular inflammation

Project Summary/Abstract The proposal outlines an integrated research and career development plan for David Wu, MD PhD, to com- plete postdoctoral training in the laboratories of Gokhan Mutlu, MD, and Yun Fang, PhD and transition to an independent academic position by establishing a research program in vascular pathophysiology with a NIH mentored career award (K99/R00). The PI has recently completed an NIH F32 fellowship (F32 HL134288) and is trained in the fields of metabolism, molecular biology, biophysics, optics, bioengineering, and vascular biolo- gy. During the 2-year mentored period (K99), the PI will receive additional academic guidance from the men- tors and the advisory committee at the University of Chicago. The career development plan is designed to equip the PI with the necessary knowledge and skills in biomedical research for a successful transition as an independent academician, leading to an R01 as the R00 phase of the work progresses. The overall research goal is to determine the role of endothelial metabolism in mediating endothelial phenotypes in relation to the initiation and propagation of acute lung injury. The role of endothelial metabolism in pro-inflammatory hemody- namical flow types is poorly understood. Preliminary studies conducted by the PI during his post-doctoral F32 phase demonstrated that low shear stress or disturbed flow hemodynamics causes endothelial cells to in- crease glycolytic metabolism, compared to unidirectional flow. Increasing this glycolysis is necessary for in- creased endothelial inflammation (eLife, 2017). The PI furthermore showed that in acute lung injury, endotheli- al cells are unable to sense hemodynamic flow, and have a phenotype that is reminiscent of disturbed flow hemodynamics (AJRCCM, 2017). This K99/R00 research proposal tests the overall hypothesis that endothelial cell dysfunction causes a change in endothelial metabolism that is critical to the initiation and progression of acute lung injury. Aim 1 will test the hypothesis that the cytoskeleton is critical for initiating localized glycolysis that powers vascular barrier breakdown by RhoA mediated release of aldolase A, a critical enzyme in the gly- colytic pathway. Aim 2 will test the hypothesis that down-regulation of oxidative phosphorylation as a conse- quence of endothelial cell dysfunction causes mitochondrial reverse electron transport, which is critical for re- active oxygen species production and upregulation of glycolysis. Aim 3 will test the hypothesis that modulating endothelial metabolism can reduce lung injury in mouse models. The goal will be achieved by integrating single cell microscopy and molecular analysis in vitro and in vivo systems, leading to a mechanistic understanding of how metabolism influences injury propagation, and perhaps uncover therapeutic targets. Attainment of this proposed career award will accelerate the transition for David Wu to an independent physician-scientist and lead to acquisition of competitive R01 funding.

项目概要/摘要 该提案概述了医学博士 David Wu 的综合研究和职业发展计划，以 在 Gokhan Mutlu 医学博士和 Yun Fang 博士的实验室完成博士后培训，并过渡到 通过与 NIH 建立血管病理生理学研究项目，获得独立的学术地位 指导职业奖（K99/R00）。 PI 最近完成了 NIH F32 奖学金 (F32 HL134288) 和 接受过新陈代谢、分子生物学、生物物理学、光学、生物工程和血管生物学领域的培训 吉。在为期 2 年的指导期间（K99），PI 将接受来自以下人员的额外学术指导： 芝加哥大学的董事和咨询委员会。职业发展计划旨在 为 PI 提供生物医学研究所需的知识和技能，以便成功过渡为 独立院士，随着 R00 阶段工作的进展，导致 R01。整体研究 目标是确定内皮代谢在介导内皮表型中的作用 急性肺损伤的发生和传播。内皮代谢在促炎性血流动力学中的作用 人们对自然流类型知之甚少。 PI在博士后F32期间进行的初步研究 相表明，低剪切应力或扰动的血流动力学会导致内皮细胞进入 与单向流动相比，糖酵解代谢增加。增加糖酵解是必要的 内皮炎症增加（eLife，2017）。 PI 还表明，在急性肺损伤中，内皮细胞 所有细胞都无法感知血流动力学流动，并且具有让人想起血流紊乱的表型 血流动力学（AJRCCM，2017）。这项 K99/R00 研究计划测试了以下总体假设：内皮细胞 细胞功能障碍导致内皮代谢的变化，这对于细胞功能障碍的发生和进展至关重要 急性肺损伤。目标 1 将检验细胞骨架对于启动局部糖酵解至关重要的假设 通过 RhoA 介导的醛缩酶 A 的释放来促进血管屏障的破坏，醛缩酶 A 是甘氨酸中的关键酶 结肠途径。目标 2 将检验氧化磷酸化下调的假设 内皮细胞功能障碍的序列导致线粒体反向电子传递，这对于重新 活性氧的产生和糖酵解的上调。目标 3 将检验以下假设：调节 内皮代谢可以减少小鼠模型的肺损伤。该目标将通过整合单一 体外和体内系统的细胞显微镜和分子分析，导致对 新陈代谢如何影响损伤传播，并可能揭示治疗目标。达到这个境界 拟议的职业奖将加速吴大卫向独立医师科学家的转变 导致获得有竞争力的 R01 资金。