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

项目摘要/摘要 心力衰竭的特征是脂肪酸氧化(FAO)减少和糖酵解增加。 增加粮农组织在心力衰竭动物模型中是有益的，但为什么有益还不清楚。粮农组织 心力衰竭期间的抑制部分是由于在缺血和缺血期间缺氧增加所致 心肌病现在占心力衰竭病例的近70%。低氧抑制的机制 粮农组织仍然知之甚少。粮农组织被划分为线粒体和过氧化物体。我有过 研究发现，HIFA是对低氧反应的主要调节者，它会耗尽过氧化酶体。从机械上讲。我 已经确定HIFA激活DEPP1，这是一种功能未知的蛋白质，对于缺氧是必要的，也是充分的- 诱导的过氧化物体丢失。在目标1中，我建议进行互补的生化和遗传实验，以确定 DEPP1介导的过氧化物体丢失的机制。在目标2中，我将确定DEPP1损失如何减少 慢性HIFA激活过程中的心肌细胞死亡。在目标3中，我建议测试DEPP1在脑缺血中的作用 心肌病动物模型。这些研究将有助于理解心力衰竭是如何抑制 并确定心力衰竭的一种新机制。 我是一名生物学家，有新陈代谢和营养感应方面的背景，申请K99奖 长期目标是成为一名终身教职的独立实验室调查员。我设想开展一项研究 计划的重点是有限氧气供应的常见病理生理学如何调节新陈代谢。 细胞、组织和组织水平最终利用这些知识来开发治疗缺血的新疗法 疾病，如心力衰竭和中风。在我提议的K99研究培训期间，我将执行指导 达纳-法伯癌症研究所(DFCI)世界氧气专家威廉·凯林博士在实验室进行的研究 感官。在这个奖项的K99阶段，我将重点确定DEPP1调解的机制 低氧诱导的过氧化物体丢失。当我过渡到这个奖项的R00阶段时，我将决定如何 维持过氧化酶体功能可减少缺血时的心脏死亡，并在动物身上测试DEPP1的作用 缺血性心肌病模型。我已经组建了一个专家科学咨询委员会来帮助指导我的 发展包括：布鲁斯·斯皮格尔曼博士(DFCI/HMS)、Jean Schaffer博士(Joslin/HMS)、Christine博士 Seidman(HMS)和John Asara博士(BIDMC/DFCI)。我相信在DFCI的培训，世界级的临床和 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。

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.