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: 6390359
• 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/6390359
• 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（来自申请人摘要的逐字）：本申请的总体目标 项目是建立两种药理学的血管生成功效， 梗死后和缺血性心脏的干预：甲状腺素类似物， 二碘甲状腺丙酸（DITPA）和心动过缓药物阿力尼定。这 目标是基于这两种药物刺激机械或 代谢因素，然后触发级联的血管生成事件， 将增强存活、肥厚心肌或 缺血心肌前三个目标将基于来自男性的数据， 大鼠，而第四个目标将利用比格犬。目标1将检验假设 用这些药物治疗不仅会刺激毛细血管网络， 还能促进阻力血管的生长，从而使冠状动脉储备正常化。 这一目标将包括各种血管生成测定，以及心肌细胞的检测。 在各种条件下的灌注和心室功能测量。目的2 将识别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， 血管内皮生长因子和转化生长因子-β， 利用原位杂交、印迹和免疫组织化学技术。 目的3关注年龄在梗死后心脏功能中的作用， 血管化的两种治疗干预的反应。使用老年人 大鼠在这一建议是特别重要的，因为心肌梗死 最常发生在老年人身上。实验方案中， 前两个目标将被用来探讨这一目标在中年和 衰老的老鼠目标4将检验关于DITPA疗效的假设， 阿力尼定促进络脉和毛细血管的生长， 缺血期间的小动脉，由逐渐的冠状动脉闭塞引起。这些 通过提供缺血模型，对比格犬的研究补充了对大鼠的研究 在一个非肥大的心脏。我们的研究致力于非侵入性治疗， 可以容易地用于患有缺血性心脏病或代偿性心脏病的人， 心肌梗死导致的肥大和重塑。等 介入与更具侵入性的介入相比具有许多优点， 例如，在一个实施例中，氧源性生长因子或基因疗法的递送。