Epigenetic control of pathologic cardiac remodeling

项目摘要/摘要 这份提案详细介绍了一项为期5年的职业发展和学术晋升培训计划。 心血管医学，医学博士，首席研究员迈克尔·A·伯克博士。伯克医生是个内科医生- 埃默里大学(欧盟)医学院的科学家。他在内科完成了临床和研究培训 通过ABIM研究途径在西北大学学习医学和心血管疾病。他 然后完成了高级心力衰竭(HF)和移植心脏病学的专科奖学金培训 布里格姆妇女医院(BWH)。最后，他完成了博士后研究奖学金在实验室 克里斯汀·E博士(研究联合导师)和乔纳森·G·塞德曼博士在2015年。伯克博士最近确立了他的 在欧盟拥有自己的实验室，在那里他正在开始一个研究和职业发展计划，该计划是根据 Ahsan Husain博士(欧盟)和Christine Seidman博士(BWH)的联合指导。侯赛因博士是一位 塞德曼博士是一名内科科学家和心血管疾病专家 遗传学家；两人都有在学术心脏病学方面培训未来领导者的广泛记录。 伯克博士的研究兴趣集中在表征调控基因的表观遗传机制 随着扩张型心肌病(DCM)向心力衰竭的进展而表达。他的长期职业目标是 将这项研究转化为心力衰竭患者的临床进展。他发表了重要的研究成果 使用扩张型心肌病的遗传模型显示心脏转录的时间变化 早期激活促纤维化信号的作用。他最近提出了新的证据，表明 表观遗传阅读器蛋白是DCM发病过程中病理基因转录的关键节点。 本研究的目的是：(1)研究特定的转化生长因子β异构体的作用。 DCM中溴结构域和端外(BET)家族的表观遗传阅读器蛋白，(2)建立可能的 转化生长因子β信号和投注之间的机制联系；以及(3)定义投注重新招募的机制 靶基因。了解这些机制将为我们提供重要的基础洞察力。 并可能揭开这种常见和病态疾病的潜在治疗靶点。 这项研究将教授伯克博士使用先进的分子技术，包括病毒载体 动物体内递送，染色质免疫沉淀测序(CHIP-SEQ)和单细胞RNA-SEQ。Dr。 伯克的职业发展计划还包括进一步加深他的科学知识的教育资源。戴维斯博士。 侯赛因、塞德曼和伯克为职业发展制定了明确的时间表，包括出版 研究，在全国会议上发言，并制定一项计划，以便他随后过渡到 独立调查员。欧盟提供的支持和这一全面的职业发展计划 将使Burke博士处于最佳地位，以便在项目结束时争取独立的赠款资金。

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.