Modulation of epigenetically controlled cardiac repair mechanisms by ethanol

描述（由申请人提供）：本申请描述了一个为期5年的培训计划，在生物医学科学的独立学术生涯的发展。PI完成了博士学位。在洛约拉大学芝加哥药理学培训和额外的博士后培训再生医学范伯格心血管研究所（FCVRI）在西北大学。FCVRI提供了一个理想的环境，将来自不同资源的专业知识融入定制的课程，以最大限度地发挥学员建立科学利基的潜力，从而可以启动成功，独立的学术生涯。这个应用程序将扩大后PI的科学和分析技能 通过独特的跨部门资源整合。该项目将评估慢性乙醇消耗如何调节内皮表观基因组，以改变急性心肌梗死（AMI）后的功能和生存结局。Raj Kishore博士（医学副教授）将指导PI的科学发展，并作为再生医学领域公认的领导者，在培养学术上成功的独立科学家方面有着令人敬畏的记录。此外，该计划还将聘请侯立凡博士（预防医学副教授）和秦刚建博士（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，几位备受推崇的生物医学科学家将与一位酒精专家（伊丽莎白·科瓦奇博士）一起组成一个发展咨询委员会，在PI的整个发展过程中提供科学和职业建议。该应用程序的重点是乙醇如何调节参与心肌缺血修复的细胞类型中的表观基因组程序。初步数据显示，慢性乙醇改变了特定基因的表达模式（即，内皮祖细胞（EPCs）中的eNOS和MMP 9：参与缺血后修复的重要细胞类型。有证据表明，慢性乙醇消耗影响AMI后的心脏功能，也改变了内皮细胞（EC）中的各种表观遗传标记。拟议的实验将利用慢性乙醇消耗模型来探索AMI后表现为改变的结果的细胞/表观遗传变化。具体目标包括：1）为了确定为什么先前慢性乙醇消耗的不同水平对AMI后的心脏功能产生不同的影响，2）为了研究乙醇对CEC/EPCs中的表观基因组指纹的调节的机制基础和功能影响，3）乙醇介导的MMP 9和eNOS表达的表观遗传调节在AMI后EPC介导的心肌修复中起什么作用？这是第一次对心脏中乙醇诱导的表观基因组调控进行机制分析，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.