The Role of Adenosine in Chronic Ischemic Cardiomyopathy

腺苷在慢性缺血性心肌病中的作用

• 批准号: 6677645
• 负责人: Dai-Trang Elizabeth Le
• 金额: $ 12.78万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6677645
• 关键词: adenosine; angiogenesis; apoptosis; cardiovascular imaging /visualization; dogs; echocardiography; electrocardiography; heart ventricle; immunocytochemistry; inflammation; inhibitor /antagonist; myocardial ischemia /hypoxia; stimulant /agonist

DESCRIPTION (provided by applicant): The candidate received superb training in myocardial contrast echocardiography (MCE) and coronary physiology research in Dr. Sanjiv Kaul's experimental laboratory and is committed to the development of an academic career in cardiovascular medicine. The K08 grant would allow her to achieve her immediate career goals, which are to continue to develop expertise in the field of MCE as new ultrasound equipment and microbubbles are developed, to gain an understanding of the pathogenesis of chronic ischemic cardiomyopathy, to learn histopathologic, immunohistochemical, ELISA, EIA, RIA, and SPA techniques, and to become familiar with cardiac MRI as a research tool. Her long-term career goals include development into an independent investigator in the experimental laboratory in the subject of chronic LV dysfunction and MCE, participation in translational research protocols with a focus on chronic ischemia and therapeutics for ischemic congestive heart failure (CHF), and practicing clinical cardiology with an emphasis on coronary artery disease and echocardiography. In sum, she is committed to developing a successful academic career in cardiovascular medicine. CHF is a major health problem in industrialized countries and its prevalence, morbidity, and mortality are rapidly rising. The pathophysiology of ischemic CHF is not well understood. The overall aim of this research proposal is to investigate the role of adenosine in chronic ischemic cardiomyopathy in a canine model of ameroid-induced left ventricular (LV) dysfunction. An A1 allosteric enhancer, a selective A2A agonist and antagonist, and a selective A3 agonist will be given to study their effects on angiogenesis, apoptosis, inflammation, vasodilation, and cardioprotection. At baseline, maximal LV dysfunction, and 1 month, 3 months, and 6 months after administration of the adenosine agonist or antagonist, we will perform MCE to examine myocardial perfusion and angiogenesis, contrast echo imaging of inflammation, MRI to examine myocardial mass, LV volume, and regional and global LV function, microspheres injection to assess myocardial blood flow, and interstitial fluid collection from the myocardium to examine the presence of cytokines and white blood cells. After the 6-month evaluation, histopathology and immunohistochemistry will be performed to correlate functional changes with histologic evidence of inflammatory changes, apoptosis, and angiogenesis. The research environment involves close mentoring by Drs. Kaul and Siragy, use of their lab space, and enthusiastic support from the division chief and consultants, including Dr. Joel Linden who is an authority on the role of adenosine in cardiovascular physiology and pharmacology.

描述(由申请人提供)： 这位候选人在Sanjiv Kaul博士的实验实验室接受了心肌声学造影(MCE)和冠状动脉生理学研究方面的精湛培训，并致力于心血管医学学术生涯的发展。K08的资助将使她能够实现她当前的职业目标，即随着新的超声设备和微泡的开发，继续发展MCE领域的专业知识，了解慢性缺血性心肌病的发病机制，学习组织病理学、免疫组织化学、ELISA、EIA、RIA和SPA技术，并熟悉作为研究工具的心脏MRI。她的长期职业目标包括在实验实验室发展成为慢性左心功能不全和慢性心肌梗死的独立研究员，参与专注于慢性缺血和缺血性充血性心力衰竭(CHF)治疗的转化性研究方案，以及从事临床心脏病学，重点是冠状动脉疾病和超声心动图。总而言之，她致力于在心血管医学领域发展成功的学术生涯。充血性心力衰竭是工业化国家的一个主要健康问题，其患病率、发病率和死亡率正在迅速上升。缺血性充血性心力衰竭的病理生理学机制尚不清楚。这项研究的总体目标是在无水乙醇诱导的左心功能不全的犬模型中，研究腺苷在慢性缺血性心肌病中的作用。A1变构增强剂、选择性A2A激动剂和拮抗剂以及选择性A3激动剂将用于研究它们在血管生成、细胞凋亡、炎症、血管扩张和心脏保护方面的作用。在基线、最大左心功能不全时，以及应用腺苷激动剂或拮抗剂后1个月、3个月和6个月，我们将进行MCE检查以检查心肌灌注和血管生成，炎症的对比回声成像，MRI检查心肌质量、左室容量、局部和整体左心功能，注射微球以评估心肌血流，并收集心肌间质液体以检查细胞因子和白细胞的存在。在6个月的评估后，将进行组织病理学和免疫组织化学检查，以将功能变化与炎性变化、细胞凋亡和血管生成的组织学证据相关联。研究环境包括Kaul博士和Siragy博士的密切指导，他们实验室空间的使用，以及部门负责人和顾问的热情支持，包括乔尔·林登博士，他是腺苷在心血管生理学和药理学中的作用方面的权威。