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A BRD4-GATA4 module cooperatively regulates mitochondrial bioenergetic homeostasis in the adult heart

BRD4-GATA4 模块协同调节成人心脏中的线粒体生物能稳态

基本信息

批准号：
10372139
负责人：
Arun Padmanabhan
金额：
$ 15.09万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10372139
关键词：
ATAC-seq Acute Address Adult Affect American Animal Model Area BRD2 gene Binding Biochemical Bioenergetics Bioinformatics Biological Assay Biology Bromodomain Cardiac Cardiac Myocytes Cardiology Cardiovascular Diseases Cardiovascular Models Cardiovascular system Cell model Cells ChIP-seq Chromatin Clinical Communication Complex Coupled Data Development Development Plans Developmental Biology Diagnosis Disease Disease model Down-Regulation Elements Energy Metabolism Enhancers Environment Epigenetic Process Equipment Family Funding GATA4 gene Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Heart Heart failure Homeostasis In Vitro Institutes K-Series Research Career Programs Knowledge Laboratories Lead Lysine Macromolecular Complexes Maps Mediating Mentors Mentorship Metabolic Mitochondria Modeling Molecular Molecular Biology Mus Mutation Neurohormones Nodal Oxidative Phosphorylation Pathogenesis Persons Phase Phenotype Physicians Process Proteins Quality of life Reader Regulation Regulator Genes Regulatory Element Research Research Personnel Research Training Rodent Role Running Scheme Scientist Series Specificity Techniques Tertiary Protein Structure Testing Therapeutic Effect Tissues Training United States Work base career career development cost defined contribution design experience heart function heart metabolism in vivo inhibitor insight interest member mitochondrial dysfunction mitochondrial metabolism mortality mouse model mutant novel novel therapeutic intervention novel therapeutics preservation programs protein complex protein function reconstitution recruit scaffold skills small molecule standard of care stem therapeutic target transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY / ABSTRACT Heart failure (HF) affects millions of people and costs over 40 billion dollars annually in the United States alone. Despite current pharmacotherapeutic approaches, which largely involve blockade of circulating neurohormone activity, a diagnosis of HF carries a 5‐year mortality rate of nearly 50% underscoring the urgent need for new treatments. The mitochondria have emerged as a central factor in the pathogenesis and progression of HF with no therapies presently available to address mitochondrial dysfunction. My goal in seeking a K08 Mentored Clinical Scientist Research Career Development Award is to acquire the necessary knowledge and practical training to make major advances in our understanding of the mechanisms underlying cardiac energy metabolism and mitochondrial function in the adult heart. I hypothesize that BRD4 (a ubiquitously expressed chromatin “reader” protein) complexes with GATA4 (a lineage determining cardiac transcription factor) to regulate a mitochondrial bioenergetic gene program in cardiomyocytes (Aim 1). I also hypothesize that GATA4 is a critical regulator of cardiac metabolism in cardiomyocytes in vivo and that this tissue-enriched transcription factor is providing specificity to the action of BRD4 (Aim 2). Finally, I hypothesize that a BRD4-GATA4 module controls the expression of PGC-1α and β, known master transcriptional regulators of mitochondrial genes, to mediate the phenotype of cardiomyocyte BRD4 loss (Aim 3). To address these aims, I will combine novel animal models that I have generated, standard in vitro biochemical approaches, and advanced molecular biology and bioinformatics techniques. My long-term goal is to develop a deeper molecular understanding of HF pathogenesis that may lead to novel therapies. My graduate training provided me with important experience in cardiovascular research, however my focus was on developmental biology. I am now directing my efforts towards studying adult cardiomyocyte homeostasis—an area of interest that emerged from my clinical training in cardiology. My research mentor has a long record of impactful discoveries using cutting-edge techniques in cellular and animal models of cardiovascular disease. The research environment at the Gladstone Institutes/UCSF is exceptional and houses state-of-the-art equipment and investigators making groundbreaking discoveries. I have assembled a team of highly accomplished mentors and advisors to guide me through this next phase of my training on the path to becoming an independent investigator. My training plan is specifically designed to provide me with mentorship and research training in bioinformatics, mouse modeling of disease, and advanced techniques in molecular biology. Beyond this, I will gain experience with other skills required to run a research group, such as scientific communication and laboratory management. Completing the research and obtaining the skill sets outlined in this proposal will prepare me well to obtain R01 or equivalent funding to begin my career as an independent investigator.

项目概要/摘要在美国，心力衰竭 (HF) 影响数百万人，每年造成的损失超过 400 亿美元独自的。尽管目前的药物治疗方法主要涉及阻断循环神经激素活性，心力衰竭的诊断导致 5 年死亡率接近 50%，这凸显了紧急情况需要新的治疗方法。线粒体已成为发病机制中的核心因素，目前尚无可用于解决线粒体功能障碍的治疗方法。我寻求 K08 指导临床科学家研究职业发展奖的目标是获得必要的知识和实践培训，以在我们对事物的理解上取得重大进展成人心脏中心脏能量代谢和线粒体功能的潜在机制。我假设 BRD4（一种普遍表达的染色质“阅读器”蛋白）与 GATA4（一种谱系确定心脏转录因子）来调节线粒体生物能基因程序心肌细胞（目标 1）。我还假设 GATA4 是心脏代谢的关键调节因子体内心肌细胞，这种富含组织的转录因子为心肌细胞的作用提供了特异性 BRD4（目标 2）。最后，我假设 BRD4-GATA4 模块控制 PGC-1α 和 β 的表达，已知线粒体基因的主要转录调节因子，介导心肌细胞的表型 BRD4 损失（目标 3）。为了实现这些目标，我将结合我生成的新动物模型、标准体外生化方法以及先进的分子生物学和生物信息学技术。我的长期目标是对心力衰竭发病机制有更深入的分子了解，这可能会带来新的治疗方法。我的研究生培训为我提供了心血管研究方面的重要经验，但是我的重点是研究发育生物学的。我现在正致力于研究成人心肌细胞体内平衡——这是我在心脏病学临床培训中产生的一个感兴趣的领域。我的研究导师有在细胞和动物模型中使用尖端技术取得的有影响力的发现的长期记录心血管疾病。格拉德斯通研究所/加州大学旧金山分校的研究环境非常优越，拥有最先进的设备和研究人员做出突破性的发现。我组建了一个团队成就卓著的导师和顾问指导我完成下一阶段的培训，走上通往成功之路成为一名独立调查员。我的培训计划是专门为我提供指导而设计的生物信息学、小鼠疾病建模以及分子先进技术方面的研究培训生物学。除此之外，我还将获得管理研究小组所需的其他技能的经验，例如科学通讯和实验室管理。完成研究并获得中概述的技能集该提案将为我获得 R01 或同等资金以开始我的独立职业生涯做好准备研究者。