Padmanabhan K08 Admin Supplement

Padmanabhan K08 管理补充资料

• 批准号: 10852749
• 负责人: Arun Padmanabhan
• 金额: $ 7.56万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10852749
• 关键词: Address; Administrative Supplement; Adult; Affect; American; Animal Model; Area; Award; Biochemical; Bioenergetics; Bioinformatics; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cell model; Chromatin; Chronic Disease; Clinical; Communication; Complex; Development; Developmental Biology; Diagnosis; Disease; Disease model; Energy Metabolism; Ensure; Environment; Equipment; Event; Funding; GATA4 gene; Genes; Genetic Transcription; Goals; Heart; Heart failure; Homeostasis; In Vitro; Institution; K-Series Research Career Programs; Knowledge; Laboratories; Life; Light; Mediating; Mentors; Mentorship; Metabolic; Mitochondria; Molecular; Molecular Biology; Myocardial Infarction; Neurohormones; Parents; Pathogenesis; Persons; Phase; Phenotype; Productivity; Proteins; Reader; Regulator Genes; Research; Research Personnel; Research Training; Resources; Running; Scientist; Specificity; Techniques; Tissues; Training; United States; Work; career; clinical training; cost; design; experience; heart metabolism; in vivo; interest; mitochondrial dysfunction; mortality; mouse model; novel; novel therapeutics; programs; skills; success; transcription factor

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 was 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. With an unusual degree of irony, I suffered a myocardial infarction in October, 2022 that was complicated by a diagnosis of HF which has slowed my progress in carrying out the aims described in my initial proposal. I am hopeful that the additional funding afforded by this Administrative Supplement will allow me to close the gap in productivity that resulted from this critical life event. Those aims are centered around the hypotheses that 1.) the ubiquitously expressed chromatin reader protein BRD4 complexes with the cardiac transcription factor GATA4 to regulate mitochondrial bioenergetic gene programs in cardiomyocytes; 2.) 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; and 3.) that a BRD4-GATA4 module controls the expression of PGC-1a and b, known master transcriptional regulators of mitochondrial genes, to mediate the phenotype of cardiomyocyte BRD4 loss. To address those aims, I have been combining novel animal models that I have generated, standard in vitro biochemical approaches, and advanced molecular biology and bioinformatics techniques. My long-term goal, which is now further motivated by my personal experience with this chronic disease, 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. In light of my recent event, my institution has provided me with additional resources and mentorship to help ensure my continued success such that I can complete the research and obtain the skill sets outlined in the initial K08 proposal, thus preparing me well to obtain R01 or equivalent funding to begin my career as an independent investigator. This Administrative Supplement will aid significantly towards that end and make certain that this unfortunate episode has no lasting adverse professional consequences.

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。带着一个 具有不同寻常的讽刺意味，我在2022年10月患上了心肌梗塞，并发了 心力衰竭的诊断减缓了我实现最初提议中描述的目标的进度。我是 希望这一行政补编提供的额外资金将使我能够弥合#年的差距 这一重要的人生事件所带来的生产力。这些目标围绕着以下假设：1) 广泛表达的染色质阅读蛋白BRD4与心脏转录因子的复合体 (1)GATA4调控心肌细胞线粒体生物能基因程序；GATA4是一个关键 在活体心肌细胞中的心脏代谢调节因子以及这种组织富集型转录因子 为BRD4的作用提供特异性；以及3.)BRD4-GATA4模块控制其表达 PGC-1a和PGC-1b是已知的线粒体基因转录调节主控基因，介导了细胞的表型。 心肌细胞BRD4缺失。为了达到这些目标，我一直在结合我所拥有的新的动物模型 产生的、标准的体外生化方法，以及先进的分子生物学和生物信息学 技巧。我的长期目标，这一目标现在进一步受到我个人患上这种慢性疾病的经验的推动 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。鉴于我最近的活动，我的机构为我提供了 额外的资源和指导，帮助确保我继续取得成功，这样我就可以完成 研究并获得初始K08建议书中概述的技能集，从而为我获得R01或 作为一名独立调查员开始我的职业生涯。这份行政副刊将有助于 并确保这一不幸事件不会有持久的不利影响 职业后果。