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

• 批准号: 10190564
• 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
• 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/10190564
• 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; 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/antagonist; 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

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.

项目摘要/摘要 心力衰竭(HF)影响着数百万人，在美国每年造成超过400亿美元的损失 独自一人。尽管目前的药物治疗方法很大程度上涉及阻断循环 神经激素活性，被诊断为心力衰竭的5年死亡率接近50%，突显了紧迫性 需要新的治疗方法。线粒体已成为发病机制中的中心因素，并 心力衰竭的进展，目前还没有治疗方法来解决线粒体功能障碍。 我寻求K08临床科学家导师研究职业发展奖的目标是获得 必要的知识和实践训练，使我们对 成人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蛋白)与GATA4(一种谱系)形成复合体 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 这种组织丰富的转录因子提供了特异性的作用于 BRD4(目标2)。最后，我假设BRD4-GATA4模块控制PGC-1α和β的表达， 已知的线粒体基因的主要转录调节因子，以调节心肌细胞的表型 BRD4损失(目标3)。为了达到这些目标，我将结合我创造的新的动物模型，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。我的长期生活 目的是加深对心力衰竭发病机制的分子理解，从而可能导致新的治疗方法。 我的研究生培训为我提供了重要的心血管研究经验，但我的重点是 是关于发育生物学的。我现在正致力于研究成人心肌细胞 动态平衡--这是我在心脏病学的临床训练中发现的一个有趣的领域。我的研究导师 在细胞和动物模型中使用尖端技术进行有影响力的发现的长期记录 心血管疾病。加州大学格拉德斯通学院/加州大学旧金山分校的研究环境特别好， 最先进的设备和调查人员取得突破性发现。我已经组建了一个团队 非常有成就的导师和顾问，指导我完成下一阶段的培训，走上 成为一名独立调查员。我的培训计划是专门为我提供指导的 以及生物信息学、疾病的老鼠模型和分子方面的高级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 沟通和实验室管理。完成研究并获得中概述的技能集 这项提议将为我获得R01或同等的资金开始我的独立职业生涯做好准备 调查员。