Modulation of epigenetically controlled cardiac repair mechanisms by ethanol

描述(由申请人提供)：本申请描述了一项为期5年的培训计划，旨在发展生物医学科学领域的独立学术生涯。他在芝加哥洛约拉大学完成了药理学博士培训，并在西北大学范伯格心血管研究所(FCVRI)完成了再生医学的博士后培训。FCVRI通过将来自不同资源的专业知识整合到定制项目中，提供了一个理想的环境，以便最大限度地发挥学员建立一个科学利基的潜力，从这个利基开始成功的、独立的学术生涯。这个应用程序将扩展PI的科学和分析技能 通过独特的部门间资源整合。该项目将评估慢性酒精消费如何调节内皮细胞表观基因组，以改变急性心肌梗死(AMI)后的功能和生存结果。Raj Kishore博士(医学副教授)将指导PI的科学发展，他是再生医学领域公认的领导者，在培训学术上成功的独立科学家方面有着令人敬畏的记录。此外，该计划将招募侯立凡博士(预防医学副教授)和秦钢健博士(医学助理教授)作为共同导师，他们都是各自领域内备受尊敬的科学家。最后，几位备受尊敬的生物医学科学家将与一位酒精专家贡献者(伊丽莎白·科瓦奇博士)一起组成一个发展咨询委员会，在PI的发展过程中提供科学和职业建议。应用的重点是乙醇如何调节参与心肌缺血修复的细胞类型的表观基因组程序。初步数据显示，慢性乙醇改变了内皮祖细胞中特定基因(即eNOS和MMP9)的表达模式，内皮祖细胞是参与缺血后修复的一种重要细胞类型。有证据表明，慢性酒精摄入会影响急性心肌梗死后的心功能，还会改变内皮细胞(ECs)的各种表观遗传标志。拟议的实验将利用慢性酒精消耗模型来探索细胞/表观遗传学变化，这些变化表现为急性心肌梗死后结果的改变。其具体目的包括：1)确定不同水平的慢性酒精摄入对急性心肌梗死后心功能产生不同影响的原因；2)研究乙醇调节CECs/EPC表观基因组指纹的机制基础和功能影响；3)乙醇介导的MMP9和eNOS表达的表观遗传调控在EPC介导的急性心肌梗死后心肌修复中扮演什么角色？这是第一次对乙醇诱导的心脏表观基因组调节进行机制分析，并使用了模拟人类患者情况的相关模型。

DESCRIPTION (provided by applicant): This application describes a 5 year training program for the development of an independent academic career in the Biomedical Sciences. The PI completed his Ph.D. training in Pharmacology at Loyola University Chicago and additional post-doctoral training in Regenerative Medicine in the Feinberg Cardiovascular Research Institute (FCVRI) at Northwestern University. The FCVRI provides an ideal setting by incorporating expertise from diverse resources into customized programs in order to maximize the potential for trainees establishing a scientific niche from which a successful, independent academic career can be launched. This application will expand upon the PI's scientific and analytical skills through a unique integration of interdepartmental resources. This program will assess how chronic ethanol consumption modulates the endothelial epigenome to alter functional and survival outcomes following acute myocardial infarction (AMI). Dr. Raj Kishore (Associate Professor of Medicine) will mentor the PI's scientific development and does so as a recognized leader in the field of Regenerative Medicine with a formidable record of training academically successful independent scientists. Additionally, the program will enlist the expertise of Dr. Lifan Hou (Associate Professor of Preventative Medicine) and Dr. Gangjian Qin (Assistant Professor of Medicine) as co- mentors, who are both well-respected scientists within their respective fields. Lastly, several highly-regarded biomedical scientists will form a developmental advisory committee alongside an expert alcohol contributor (Dr. Elizabeth Kovacs) to provide scientific and career advice throughout the PI's development. The application focuses on how ethanol modulates the epigenomic programs in cell types involved in myocardial ischemic repair. Preliminary data reveals that chronic ethanol alters expression patterns of specific genes (i.e., eNOS and MMP9) in endothelial progenitor cells (EPCs): an important cell type involved in post-ischemic repair. Evidence shows that chronic ethanol consumption impacts cardiac function following an AMI and also alters various epigenetic marks in endothelial cells (ECs). Proposed experiments will utilize a chronic ethanol consumption model to explore cellular/epigenetic changes that manifest as altered outcomes following AMI. The specific aims include: 1) To determine why disparate levels of prior chronic ethanol consumption produce differential effects on cardiac function following AMI, 2) To investigate the mechanistic basis and functional impact of ethanol's modulation of the epigenomic fingerprint in CECs/EPCs, 3) What role does ethanol-mediated epigenetic regulation of MMP9 and eNOS expression play in EPC-mediated myocardial repair following AMI? This is the first mechanistic analysis of ethanol-induced epigenomic regulation in the heart and uses relevant models that mimic the circumstances of human patients.