CORONARY BLOOD VESSELS AND HEART DISEASE

冠状血管和心脏病

• 批准号: 6032584
• 负责人: THOMAS N SATO
• 金额: $ 34.33万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6032584
• 关键词: angiogenesis; angiogenesis factor; angiogenesis inhibitors; biological signal transduction; coronary occlusion /thrombosis; coronary vessels; developmental genetics; gene expression; genetically modified animals; laboratory mouse; protein tyrosine kinase; tissue /cell culture; vascular endothelial growth factors; vascular endothelium

The long-term objectives are to understand how the morphogenesis and the physiological functions of coronary blood vessels are controlled at the molecular level, and to contribute to the translation of our findings into novel and effective therapeutics for a number of heart diseases. Normal morphogenesis and physiological functions of coronary vessels are critically required for the physiological functions of the heart. Therefore, it may be possible to treat diseased heart conditions by restoring normal morphogenesis and physiological functions of coronary vessels. The specific aims of this proposal are: 1) to test the hypothesis that angiopoietin-1 alone, or angiopoietin-1 with VEGF can effectively enhance coronary angiogenesis, and as a result, can bring a functional benefit to the cardiac adaptation in response to the surgically induced coronary vessel occlusion, 2) to test the hypothesis that the deficiency of an anti- angiogenic factor, angiopoietin-2, leads to enhanced coronary angiogenesis during the cardiac adaptation in response to the surgically induced coronary vessel occlusion, 3) to test the hypothesis that the Akt intracellular signaling pathway is essential and/or sufficient for the angiopoietin-1-induced endothelial sprouting and vessel tubulogenesis in the three- dimensional fibrin gel culture system, an in vitro assay system related to the vessel morphogenesis in vivo, and 4) to test the hypothesis that coronary endothelial cells express a unique set of genes that are essential for the mature physiological functions of coronary vessels. We will accomplish these goals by extensive use of transgenic mice, knock-out mice, sophisticated small animal surgical method, quantitative and qualitative morphometric analyses, a state-of-the-art, non-invasive imaging method, an unique cell culture system, biochemical methods, and molecular biological methods. Upon the completion of these projects we will be able to provide comprehensive in vivo evaluations of the degree of usefulness of angiopoietins and their downstream signaling pathway components in therapeutic angiogenesis. This will have an immediate impact on the improvement of the current strategies for therapeutic angiogenesis in the heart. Furthermore, our studies may provide useful molecular insights into the novel aspects of the physiological functions of coronary vessels. This information may potentially have a future impact on how to enhance the maturation of the physiological functionality of these vessels, a goal where therapies based on angiogenesis alone may fall short.

长期目标是了解如何在分子水平控制冠状动脉血管的形态发生和生理功能，并为我们的发现转化为多种心脏病的新型有效疗法。 心脏的生理功能至关重要的是冠状动脉血管的正常形态发生和生理功能。因此，可以通过恢复冠状动脉血管的正常形态发生和生理功能来治疗患病的心脏病。 该提案的具体目的是：1）检验以下假设：单独使用血管生成素-1或具有VEGF的血管生成素-1可以有效增强冠状动脉生成，因此可以为心脏适应带来功能益处，以响应于手术诱导的冠状动脉血管囊肿，2）下降，2）血管生成素-2，导致心脏适应过程中对手术诱导的冠状血管闭塞的冠状动脉血管生成增强，3）测试Akt细胞内信号传导途径是必不可少的和/或足以使Akt内的脉络膜结构诱导的内膜纤维构造构成的构造的三个构成构造的构型构成的三个稳定的构造，以体内血管形态发生相关的体外测定系统，以及4）测试冠状动脉内皮细胞表达独特基因的假设，这对于冠状血管的成熟生理功能至关重要。 我们将通过广泛使用转基因小鼠，敲除小鼠，精致的小动物手术方法，定量和定性形态计量学分析，一种最先进的非侵入性成像方法，独特的细胞培养系统，生化方法和分子生物学方法来实现这些目标。这些项目完成后，我们将能够对血管生成素及其下游信号通路成分在治疗性血管生成中的有用程度进行全面的体内评估。 这将立即影响心脏治疗性血管生成的当前策略。 此外，我们的研究可能会为冠状动脉血管生理功能的新方面提供有用的分子见解。 该信息可能会对如何增强这些血管生理功能的成熟产生未来的影响，这个目标仅基于血管生成的疗法可能会降低。