Modulation of epigenetically controlled cardiac repair mechanisms by ethanol

摘要摘要 这份提案描述了一项为期5年的培养独立学者的培训计划。 生物医学科学方面的职业生涯。PI在洛约拉大学完成了他的药理学博士培训 芝加哥大学和范伯格心血管学院再生医学博士后额外培训 西北大学研究所(FCVRI)。FCVRI通过以下方式提供理想的环境 将来自不同资源的专业知识转化为定制计划，以最大限度地发挥学员的潜力 建立一个科学利基，从那里开始一个成功的、独立的学术生涯。 这项提议将通过独特的集成来扩展PI的科学和分析技能 跨部门资源。这个项目将评估长期的乙醇消费是如何调节 内皮表观基因组改变急性心肌梗死(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，并作为 再生医学领域公认的领导者，在学术上有令人敬畏的培训记录 成功的独立科学家。此外，该计划还将征集侯丽芳博士的专业知识 (预防医学副教授)和秦钢健博士(医学助理教授)共同担任 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酒精专家贡献者(Dr。 伊丽莎白·科瓦奇)在PI的整个发展过程中提供科学和职业建议。 研究方案集中在乙醇如何调节细胞类型中的表观基因组程序 参与心肌缺血修复。初步数据显示，慢性乙醇改变了表达模式 内皮祖细胞中的特异性基因(即eNOS和MMP9)：一种重要的细胞类型 在缺血后修复中。有证据表明，长期饮酒会影响以下心脏功能 急性心肌梗死还会改变内皮细胞(ECs)的各种表观遗传标志。拟议的实验将利用一种 慢性酒精摄入模型探索表现为结果改变的细胞/表观遗传学变化 急性心肌梗死后。具体目标包括：1)确定为什么先前慢性酒精的水平不同 消费对急性心肌梗死后心功能的不同影响，2)探讨其机制 乙醇调节CECs/EPC表观基因组指纹的基础和功能影响，3)什么作用 乙醇对EPC介导的心肌MMP9和eNOS表达的表观遗传调控作用 急性心肌梗死后修复？这是首次对乙醇诱导的表观基因组调控的机制进行分析。 心脏，并使用相关模型，模拟人类患者的情况。

SUMMARY ABSTRACT This proposal describes a 5 year training program for the development of an independent academic career in the Biomedical Sciences. The PI completed his PhD 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 proposal 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. Lifang 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 research proposal 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.