Mechanistic Understanding of Hypoxia-Induced Peroxisome loss: Implications for Heart Failure

缺氧引起的过氧化物酶体损失的机制理解：对心力衰竭的影响

基本信息

批准号：
10840053
负责人：
Greg Wyant
金额：
$ 24.9万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10840053
关键词：
Acute Address Advisory Committees Animal Model Autophagocytosis Award Binding Proteins Biochemical Cardiac Death Cardiac Myocytes Cell Death Cessation of life Chronic Clinical Consumption Dana-Farber Cancer Institute Data Data Set Development Disease Drug Targeting Environment Experimental Genetics Functional disorder Genes Genetic Screening Glycolysis Goals Heart failure Hip region structure Hypoxia Hypoxia Inducible Factor In Vitro Ischemia Knowledge Laboratories Maintenance Measures Mediating Mentors Metabolic Metabolism Mitochondria Myocardial Ischemia Myocardial dysfunction Natural History Organelles Oxygen Pathway interactions Phase Plasma Premature Mortality Process Proteins Reperfusion Injury Repression Research Research Personnel Research Training Role Severities Stroke Supplementation Testing Therapeutic Tissues Training career detection of nutrient experimental study fatty acid oxidation heart function improved in vivo insight ischemic cardiomyopathy metabolome mouse model novel novel marker novel therapeutic intervention novel therapeutics peroxisome pre-clinical prevent programs receptor recruit response symposium tenure track transcription factor

项目摘要

Project Summary/Abstract Heart failure is characterized by decreased fatty acid oxidation (FAO) and increased glycolysis. Increasing FAO is beneficial in animal models of heart failure however why it is beneficial is unclear. FAO inhibition during heart failure occurs in part due to increased hypoxia during ischemia and ischemic cardiomyopathy now accounts for nearly 70% of heart failure cases. The mechanisms by which hypoxia inhibits FAO remain poorly understood. FAO is compartmentalized into mitochondria and peroxisomes. I have discovered that HIFa, the master regulator in the response to hypoxia, depletes peroxisomes. Mechanistically. I have identified HIFa activates DEPP1, a protein of unknown function that is necessary and sufficient for hypoxia- induced peroxisome loss. In Aim 1, I propose complementary biochemical and genetic experiments to identify the mechanism of DEPP1-mediated peroxisome loss. In Aim 2, I will determine how DEPP1 loss reduces cardiomyocyte death during chronic HIFa activation. In Aim 3, I propose to test the role of DEPP1 in ischemic cardiomyopathy animal models. These studies will contribute to the understanding of how heart failure inhibits FAO and identify a novel mechanism in heart failure. I am a biologist with a background in metabolism and nutrient sensing, applying for a K99 award with the long-term goal of becoming a tenure-track, independent laboratory investigator. I envision developing a research program focused on how the common pathophysiology of limited oxygen availability regulates metabolism at the cellular, tissue, and organismal level to ultimately harness that knowledge to develop new therapies for ischemic diseases, such as heart failure and stroke. During my proposed K99 research training, I will perform mentored research in the lab of Dr. William Kaelin at the Dana-Farber Cancer Institute (DFCI), a world’s expert in oxygen sensing. In the K99 phase of this award, I will focus on identifying the mechanism by which DEPP1 mediates hypoxia-induced peroxisome loss. As I transition into the R00 phase of this award, I will determine how maintaining peroxisome function reduces cardiac death during ischemia and test the role of DEPP1 in animal models of ischemic cardiomyopathy. I have assembled an expert scientific advisory committee to help guide my development including: Dr. Bruce Spiegelman (DFCI/HMS), Dr. Jean Schaffer (Joslin/HMS), Dr. Christine Seidman (HMS), and Dr. John Asara (BIDMC/DFCI). I believe that training at DFCI, a world-class clinical and research environment, along with additional coursework and conferences will help me achieve my long-term career goals.

项目概要/摘要心力衰竭的特征是脂肪酸氧化（FAO）减少和糖酵解增加。增加FAO对心力衰竭动物模型有益，但其为何有益尚不清楚。心力衰竭期间的抑制部分是由于缺血和缺血期间缺氧增加所致目前，心肌病占心力衰竭病例的近 70%。缺氧抑制的机制。我对FAO仍然知之甚少。FAO分为线粒体和过氧化物酶体。发现 HIFa（缺氧反应的主要调节剂）会消耗过氧化物酶体 I。已经确定 HIFa 激活 DEPP1，这是一种功能未知的蛋白质，对于缺氧是必要且充分的在目标 1 中，我建议进行互补的生化和遗传实验来识别。 DEPP1 介导的过氧化物酶体损失的机制在目标 2 中，我将确定 DEPP1 损失如何减少。在目标 3 中，我建议测试 DEPP1 在缺血中的作用。这些研究将有助于了解心力衰竭如何抑制。粮农组织并确定了一种治疗心力衰竭的新机制。我是一位具有新陈代谢和营养传感背景的生物学家，正在申请 K99 奖我的长期目标是成为一名终身教授、独立的实验室研究员，我设想开展一项研究。计划重点关注有限氧气供应的常见病理生理学如何调节新陈代谢细胞、组织和生物水平，最终利用这些知识来开发缺血性新疗法在我提议的 K99 研究培训期间，我将接受指导。达纳法伯癌症研究所 (DFCI) 世界氧气专家 William Kaelin 博士实验室的研究在本次奖励的 K99 阶段，我将重点研究 DEPP1 的介导机制。当我过渡到该奖项的 R00 阶段时，我将确定如何进行缺氧引起的过氧化物酶体损失。维持过氧化物酶体功能可减少缺血期间的心源性死亡并测试 DEPP1 在动物中的作用我组建了一个专家科学咨询委员会来帮助指导我的缺血性心肌病模型。开发人员包括：Bruce Spiegelman 博士 (DFCI/HMS)、Jean Schaffer 博士 (Joslin/HMS)、Christine 博士 Seidman (HMS) 和 John Asara 博士 (BIDMC/DFCI) 我相信 DFCI 是世界一流的临床和培训机构。研究环境以及额外的课程和会议将帮助我实现我的长期目标职业目标。