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

项目总结/摘要 心力衰竭的特征在于脂肪酸氧化（FAO）减少和糖酵解增加。 增加FAO在心力衰竭的动物模型中是有益的，但是为什么它是有益的尚不清楚。粮农组织 心力衰竭期间的抑制部分地由于缺血和缺血性心脏病期间增加的缺氧而发生。 心肌病现在占心力衰竭病例的近70%。缺氧抑制 人们对粮农组织仍然知之甚少。FAO分为线粒体和过氧化物酶体。我有 发现HIF α，缺氧反应的主要调节因子，消耗过氧化物酶体。机械地。我 已经确定HIF α激活DEPP 1，DEPP 1是一种功能未知的蛋白质，是缺氧所必需和充分的- 引起过氧化物酶体损失。在目标1中，我提出了补充的生化和遗传实验，以确定 DEPP 1介导的过氧化物酶体丢失的机制。在目标2中，我将确定DEPP 1损失如何减少 慢性HIF α激活期间的心肌细胞死亡。在目标3中，我提出测试DEPP 1在缺血性脑损伤中的作用。 心肌病动物模型。这些研究将有助于理解心力衰竭如何抑制 粮农组织和确定一个新的机制，在心力衰竭。 我是一名生物学家，有新陈代谢和营养感测的背景，申请K99奖， 长期目标是成为一名终身制的独立实验室研究员。我设想开展一项研究 该计划的重点是如何共同的病理生理学有限的氧气供应调节代谢在 细胞、组织和生物体水平，最终利用这些知识开发缺血性疾病的新疗法。 疾病，如心脏衰竭和中风。在我提议的K99研究培训期间，我将在 丹娜-法伯癌症研究所（DFCI）的威廉·凯林博士的实验室里进行的一项研究， 感应在本研究的K99阶段，我将重点研究DEPP 1的调节机制 缺氧引起的过氧化物酶体丢失。当我过渡到该奖项的R 00阶段时，我将决定如何 维持过氧化物酶体功能减少缺血期间的心脏死亡并在动物中测试DEPP 1的作用 缺血性心肌病模型。我已经召集了一个专家科学咨询委员会来帮助指导我的 开发人员包括：布鲁斯Spiegelman博士（DFCI/HMS）、Jean Schaffer博士（Joslin/HMS）、克莉丝汀博士 Seidman（HMS）和John Asara博士（BIDMC/DFCI）。我相信，在DFCI，一个世界级的临床和 研究环境，沿着额外的课程和会议将帮助我实现我的长期 职业目标。

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.