Epigenetic control of pathologic cardiac remodeling

病理性心脏重塑的表观遗传控制

基本信息

批准号：
9892027
负责人：
Michael A Burke
金额：
$ 16.08万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892027
关键词：
Affect Animals Attenuated Biology Bromodomain Calcium Cardiac Cardiac Myocytes Cardiology Cardiovascular Diseases Cardiovascular system Career Mobility Cell Compartmentation Cells Cessation of life ChIP-seq Clinical Clinical Research Country Cultured Cells Data Development Development Plans Dilated Cardiomyopathy Disease Distal Doctor of Medicine Echocardiography Epigenetic Process Family Fellowship Fibroblasts Fibrosis Functional disorder Funding Future Gene Expression Gene Proteins Gene Targeting Genes Genetic Models Genetic Transcription Goals Grant Heart Heart Transplantation Heart failure Histology Hospitals In Vitro Individual Internal Medicine Knowledge Laboratories Left Link Malignant Neoplasms Mediating Medicine Mentors Mentorship Methodology Modality Modeling Molecular Mus Mutation Myocardial dysfunction Nodal Pathologic Pathway Analysis Pathway interactions Patients Phenotype Physicians Population Positioning Attribute Postdoctoral Fellow Pre-Clinical Model Program Development Proliferating Protein Isoforms Proteins Publications Publishing Reader Research Research Personnel Research Proposals Research Training Role Scientist Signal Transduction Small Interfering RNA Stimulus Structure Techniques Testing Therapeutic TimeLine Tissues Training Training Programs Transcriptional Regulation Transforming Growth Factor beta Transgenic Mice Translating United States Universities Up-Regulation Ventricular Ventricular Remodeling Viral Vector Woman career career development chemical genetics chromatin immunoprecipitation drug development education resources epigenome experimental study familial dilated cardiomyopathy genetic approach in silico in vivo innovation insight interest knock-down medical schools meetings mouse model neutralizing antibody novel therapeutics phospholamban premature proband professor programs promoter protein expression recruit research and development single-cell RNA sequencing therapeutic target transcription factor transcriptome sequencing

项目摘要

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.

项目摘要/摘要该建议详细介绍了一项为期5年的职业发展和学术发展培训计划主要调查员Michael A. Burke博士的心血管医学。伯克博士是一个身体上的埃默里大学（EU）医学院的科学家。他完成了内部临床和研究培训西北大学通过ABIM研究途径的医学和心血管疾病。他然后完成了晚期心力衰竭（HF）和移植心脏病学的亚科奖学金培训 Brigham and妇女医院（BWH）。最后，他在实验室完成了博士后研究奖学金博士。克里斯汀·E（研究联合学）和乔纳森·塞德曼（Jonathan G. Seidman）于2015年。伯克博士最近建立了他的他在欧盟拥有实验室，在那里他正在开始研究和职业发展计划博士的结合心态。 Ahsan Husain（EU）和Christine Seidman（BWH）。侯赛因博士是医学和心肌细胞生物学专家和Seidman博士是身体科学家和心血管遗传学家；两者都有培训学术心脏病学领导者的广泛记录。伯克博士的研究兴趣着重于表征调节基因的表观遗传机制扩张心肌病（DCM）向HF的进展。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使用DCM的遗传模型证明心脏转录的暂时变化，该模型暗示了钥匙促纤维化信号的早期激活的作用。他最近产生了新的证据，表明表观读取子蛋白是DCM进展中病理基因转录的关键点。该研究建议的目标是（1）表征特定TGFβ同工型的作用和 DCM中的表观遗传学读取器蛋白的溴化域和外部（BET）家族，（2）以建立可能 TGFβ信号传导与赌注之间靶基因。了解这些机制将为生物学提供重要的基本见解 HF并可以为这种常见和病态疾病释放潜在的治疗靶标。这项研究将教伯克博士使用高级分子技术，包括病毒载体在动物中递送，染色质免疫沉淀与测序（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，以进一步发展他的科学知识。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，在国家会议上的演讲以及他随后过渡到的计划独立研究者。欧盟提供的支持和这项全面的职业发展计划将在计划期结束之前最佳地定位伯克博士以争夺独立的赠款资金。