ANGIOGENIC THERAPY FOR INFARCTED AND ISCHEMIC HEART

梗塞和缺血性心脏的血管生成疗法

• 批准号: 6194173
• 负责人: ROBERT J TOMANEK
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6194173
• 关键词: age difference; angiogenesis; angiogenesis factor; animal old age; antiarrhythmic agent; dogs; fibroblast growth factor; immunocytochemistry; in situ hybridization; laboratory rat; mature animal; myocardial ischemia /hypoxia; thyroxine analog; transforming growth factors; vascular endothelial growth factors

DESCRIPTION (Verbatim from Applicant's Abstract): The overall goal of this project is to establish the angiogenic efficacy of two pharmacological interventions in the postinfarcted and ischemic heart: a thyroxine analog, diiodothyropropionic acid (DITPA), and the bradycardic drug, alinidine. This goal is based on the rationale that these two agents stimulate mechanical or metabolic factors which then trigger the cascade of angiogenic events which will enhance myocardial perfusion in surviving, hypertrophic myocardium, or in tahe ischemic myocardium. The first three aims will be based on data from male rats, while the fourth aim will utilize beagles. Aim 1 will test the hypothesis that treatment with these agents will stimulate not only the capillary network, but also the growth of resistance vessels, thus normalizing coronary reserve. This aim will include a variety of angiogenic assays, as well as myocardial perfusion and ventricular function measurements under various conditions. Aim 2 will identify the spatial and temporal expression of growth factors which regulate the angiogenic response, e.g., basic fibroblast growth factor, vascular endothelial growth factor, and transforming growth factor-beta by utilizing in situ hybridization, blotting, and immunohistochemical techniques. Aim 3 focuses on tahe role of aging in the postinfarcted heart's ability to vascularize in response to the two therapeutic interventions. The use of aged rats in this proposal is of particular importance since myocardial infarction occurs most frequently in older individuals. The experimental protocols in the first two aims will be utilized to explore this aim in middle-aged and senescent rats. Aim 4 will test hypotheses regarding the efficacy of DITPA and alinidine in stimulating growth of collaterals as well as capillaries and arterioles during ischemia, induced by gradual coronary artery occlusion. These studies in beagles compliment the rat studies, by providing a model of ischemia in a non-hypertrophic heart. Our studies addresss non-invasive therapies which may be readily used in humans with ischemic heart disease or with compensatory hypertrophy and remodeling resulting from myocardial infarction. Such interventions have a number of advantages over more invasive interventions, e.g., the delivery of oxogenous growth factors or gene therapy.

描述（逐字研究来自申请人的摘要）：此的总体目标 项目是建立两种药理的血管生成功效 对后感染和缺血性心脏的干预措施：甲状腺素类似物， 二二硫代丙酸（DITPA）和心动过心药物Alinidine。这 目标是基于这样的理由，即这两个代理刺激机械或 代谢因子然后触发一系列血管生成事件 将增强生存，肥厚心肌或中的心肌灌注 塔赫缺血性心肌。前三个目标将基于男性的数据 大鼠，而第四个目标将利用小猎犬。 AIM 1将检验假设 用这些药物的治疗不仅会刺激毛细管网络，还会刺激 还有电阻容器的生长，从而使冠状动脉储备标准化。 此目标将包括各种血管生成测定以及心肌 在各种条件下的灌注和心室功能测量。目标2 将确定生长因子的空间和时间表达 调节血管生成反应，例如碱性成纤维细胞生长因子， 血管内皮生长因子，并通过 利用原位杂交，印迹和免疫组织化学技术。 AIM 3重点介绍衰老的角色， 响应两种治疗干预措施的血管化。老化的使用 自从心肌梗塞以来，此提案中的大鼠特别重要 在老年人中最常发生。实验方案 前两个目标将用于探索中年和 衰老的老鼠。 AIM 4将检验有关DITPA和 艾琳定（Alinidine 缺血期间的小动脉，由逐渐冠状动脉阻塞引起。这些 小猎犬的研究通过提供缺血模型来补充大鼠研究 在非嗜性心脏中。我们的研究解决了非侵入性疗法 可能很容易在患有缺血性心脏病的人或代偿性 肥大和重塑是由心肌梗塞产生的。这样的 干预措施比更多的入侵干预措施具有许多优势， 例如，氧源生长因子或基因疗法的递送。