Epigenetic control of pathologic cardiac remodeling

项目总结/摘要 该提案详细介绍了一个为期5年的职业发展和学术进步的培训计划 心血管药物的Michael A.伯克，医学博士，首席调查员伯克医生是个内科医生- 埃默里大学（欧盟）医学院的科学家。他在内部完成了临床和研究培训 医学和心血管疾病在西北大学通过ABIM研究途径。他 然后完成了高级心力衰竭（HF）和移植心脏病学的亚专业奖学金培训， 布里格姆妇女医院（BWH）最后，他完成了博士后研究奖学金的实验室， Drs.克莉丝汀E.（研究共同导师）和乔纳森G。塞德曼在2015年。伯克博士最近建立了他的 他在欧盟拥有自己的实验室，在那里他正在进行一项研究和职业发展计划， Ahsan Husain博士（欧盟）和克莉丝汀·塞德曼博士（BWH）的联合指导。侯赛因博士是一位教授， 医学和专家在心肌细胞生物学和塞德曼博士是一个内科医生，科学家和心血管 遗传学家;两人都有培养未来学术心脏病学领导者的广泛记录。 伯克博士的研究兴趣集中在表征调节基因的表观遗传机制。 扩张型心肌病（DCM）进展为HF。他的长期职业目标是 将这项研究转化为HF患者的临床进展。他发表了重要的研究成果 使用DCM的遗传模型证明心脏转录的时间变化， 早期激活促纤维化信号传导的作用。他最近提出了新的证据， 表观遗传阅读蛋白是DCM进展中病理基因转录的关键节点。 本研究的目的是（1）描述特定TGFβ亚型的作用， （2）DCM中表观遗传阅读器蛋白的布罗莫结构域和末端外（BET）家族，以建立可能的 TGFβ信号传导和BET之间的机制联系，以及（3）定义BET募集的机制， 目标基因。了解这些机制将提供重要的基本见解的生物学 HF和可能解锁潜在的治疗目标，这种常见的和病态的疾病。 这项研究将教会伯克博士使用先进的分子技术，包括病毒载体 在动物中的递送、染色质免疫沉淀测序（ChIP-seq）和单细胞RNA-seq。博士 伯克的职业发展计划还包括教育资源，以进一步他的科学知识。Drs. 侯赛因、塞德曼和伯克为职业发展制定了明确的时间轴，包括出版 进行研究，在国家会议上发言，并为他随后过渡到 独立调查员欧盟提供的支持和这一全面的职业发展计划 Burke在项目结束前竞争独立赠款资金。

Project Summary/Abstract This proposal details a 5-year training program for career development and advancement in academic cardiovascular medicine for Dr. Michael A. Burke, M.D., the principle investigator. Dr. Burke is a physician- scientist at Emory University (EU) School of Medicine. He completed clinical and research training in Internal Medicine and Cardiovascular Diseases at Northwestern University through the ABIM research pathway. He then completed subspecialty fellowship training in Advanced Heart Failure (HF) and Transplant Cardiology at Brigham and Women's Hospital (BWH). Finally, he completed a post-doctoral research fellowship in the lab of Drs. Christine E. (study co-mentor) and Jonathan G. Seidman in 2015. Dr. Burke has recently established his own laboratory at EU where he is embarking on a research and career development program under the combined mentorship of Drs. Ahsan Husain (EU) and Christine Seidman (BWH). Dr. Husain is a professor of medicine and expert in cardiomyocyte biology and Dr. Seidman is a physician-scientist and cardiovascular geneticist; both have an extensive track record of training future leaders in academic cardiology. Dr. Burke's research interest focuses on characterizing the epigenetic mechanisms that regulate gene expression with progression of dilated cardiomyopathy (DCM) to HF. His long-term career goals are to translate this research into clinical advances for patients with HF. He has published important research demonstrating temporal changes in cardiac transcription using a genetic model of DCM that suggests a key role for early activation of pro-fibrotic signaling. He has recently generated new evidence suggesting that epigenetic reader proteins are a key nodal point for pathologic gene transcription in the progression of DCM. The objectives of this research proposal are (1) to characterize the roles of specific TGFβ isoforms and the bromodomain and extraterminal (BET) family of epigenetic reader proteins in DCM, (2) to establish a possible mechanistic link between TGFβ signaling and BETs, and (3) to define the mechanism of BET recruitment to target genes. Understanding these mechanisms will provide important fundamental insight into the biology of HF and could unlock potential therapeutic targets for this common and morbid disease. This research will teach Dr. Burke the use of advanced molecular techniques including viral vector delivery in animals, chromatin immunoprecipitation with sequencing (ChIP-seq) and single-cell RNA-seq. Dr. Burke's career development plan also includes educational resources to further his scientific knowledge. Drs. Husain, Seidman and Burke have formulated a clear timeline for career development, including publication of research, presentations at national meetings and development of a plan for his subsequent transition to independent investigator. The support provided by EU and this comprehensive career development program will optimally position Dr. Burke to compete for independent grant funding by the end of the program period.