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 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 线粒体已成为发病机制的核心因素，并且需要新的治疗方法。 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。 具有不同寻常的讽刺意味的是，我在 2022 年 10 月患了心肌梗塞，并因心脏病而并发。 心力衰竭的诊断减缓了我实现最初建议中描述的目标的进度。 希望本行政补充提供的额外资金将使我能够缩小差距 这些目标围绕以下假设：1.) 普遍表达的染色质读取蛋白 BRD4 与心脏转录因子复合物 GATA4 调节心肌细胞中的线粒体生物能基因程序；2.) GATA4 是一个关键因素 体内心肌细胞心脏代谢的调节因子，这种富含组织的转录因子 提供 BRD4 作用的特异性；以及 3.) BRD4-GATA4 模块控制 PGC-1a 和 b，已知的线粒体基因的主要转录调节因子，介导表型 为了实现这些目标，我一直在结合我拥有的新动物模型。 生成的标准体外生化方法以及先进的分子生物学和生物信息学 我的长期目标现在进一步受到我对这种慢性病的个人经历的推动。 疾病，是为了对心力衰竭发病机制进行更深入的分子了解，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 我当时的研究方向是发育生物学。 体内平衡——我的研究导师在心脏病学临床培训中产生的一个感兴趣的领域。 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 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，并且拥有良好的研究环境。 我组建了一支由最先进的设备和做出突破性发现的研究人员组成的团队。 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 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 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。 根据我最近的事件，我的机构为我提供了沟通和实验室管理。 额外的资源和指导，以帮助确保我持续成功，以便我能够完成 研究并获得最初 K08 提案中概述的技能组合，从而为我获得 R01 或 R01 做好充分准备 这份行政补充文件将有助于我开始作为一名独立调查员的职业生涯。 并确保这一不幸的事件不会产生持久的不利影响 职业后果。