The Role of Adenosine in Chronic Ischemic Cardiomyopathy

描述（由申请人提供）： 该候选人在Sanjiv Kaul博士的实验室接受了心肌造影超声心动图（MCE）和冠状动脉生理学研究方面的出色培训，并致力于心血管医学学术事业的发展。K08赠款将使她实现她的直接职业目标，这是继续发展专业知识在MCE领域的新的超声设备和微泡的开发，获得慢性缺血性心肌病的发病机制的理解，学习组织病理学，免疫组织化学，ELISA，EIA，RIA和SPA技术，并成为熟悉心脏MRI作为研究工具。她的长期职业目标包括发展成为实验室中慢性LV功能障碍和MCE主题的独立研究者，参与转化研究方案，重点关注慢性缺血和缺血性充血性心力衰竭（CHF）的治疗，并实践临床心脏病学，重点是冠状动脉疾病和超声心动图。总之，她致力于发展心血管医学的成功学术生涯。CHF是工业化国家的主要健康问题，其患病率、发病率和死亡率正在迅速上升。缺血性CHF的病理生理机制尚未完全了解。本研究的总体目标是在Ameroid诱导的左心室（LV）功能障碍的犬模型中研究腺苷在慢性缺血性心肌病中的作用。将给予A1变构增强剂、选择性A2A激动剂和拮抗剂以及选择性A3激动剂以研究它们对血管生成、凋亡、炎症、血管舒张和心脏保护的作用。在基线、最大LV功能障碍以及腺苷激动剂或拮抗剂给药后1个月、3个月和6个月，我们将进行MCE以检查心肌灌注和血管生成，进行炎症的造影剂回波成像，进行MRI以检查心肌质量、LV体积以及局部和整体LV功能，进行微球注射以评估心肌血流量，以及从心肌收集间质液以检查细胞因子和白色血细胞的存在。6个月评价后，将进行组织病理学和免疫组织化学，以将功能变化与炎症变化、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和Siragy博士的密切指导，使用他们的实验室空间，以及部门负责人和顾问的热情支持，包括Joel林登博士，他是腺苷在心血管生理学和药理学中作用的权威。

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.