Engineering Effective Revascularization Strategies for Ischemia in Disease States

描述(由申请人提供) 摘要：为疾病状态下的缺血设计有效的血运重建技术慢性心肌缺血症在美国影响着2700多万患者，是发达国家发病率和死亡率的主要原因。周围性脑缺血在美国65岁及以上人群中更为普遍，占总人口的12-20%。缺血性疾病最常见的原因是由于长期的动脉粥样硬化性疾病过程导致动脉变窄。这种动脉重塑导致血流量减少，最终导致器官功能障碍和衰竭。目前治疗缺血的治疗方法包括使用经皮介入治疗来物理地打开动脉，或者使用外科方法将血流改道到血流不好的组织。这些方法有很大的局限性，从长远来看最终是失败的。治疗缺血性疾病最有效的方法是通过刺激天然血管系统的发展来使组织血运重建。许多研究试图利用生长因子、生长因子基因和移植细胞来促进缺血组织的血运重建。虽然这些治疗方法在实验模型中是有效的，但临床试验表明，它们在治疗人类疾病方面的效果有限。这项建议旨在了解为什么基于生长因子的疗法未能治疗患者的缺血，并寻求创造新的疗法来增加生长因子在这方面的有效性。我们的基本假设是，这些治疗失败的原因是，患有长期疾病和耗尽代偿机制的组织无法通过适当的生长因子信号做出反应。通过对病变细胞和组织的基础研究，我们将对信号通路进行详细的分析，以确定生长因子信号转导无效的原因。我们最近开发了新的技术，允许替换细胞表面缺失的受体和辅助受体。利用这些和其他创新方法，我们将寻求新的治疗药物配方，这些药物配方可以用作共同治疗，使生长因子在临床疾病出现时有效。我们将在临床相关的外周和心肌缺血动物模型中测试这些新的治疗方法。总之，进行的研究和开发的工具将增加我们对组织如何对血运重建疗法产生抵抗力的理解，并可能导致对这种广泛存在的、使人虚弱的疾病进行更有效的治疗。 公共卫生相关性：慢性心肌缺血疾病在美国影响着大约2700万患者，是发达国家发病率和死亡率的主要原因。周围性脑缺血在美国65岁及以上人群中更为普遍，占总人口的12-20%。这项建议试图了解为什么基于生长因子的疗法未能治疗患者的缺血，并寻求创造新的疗法来增加生长因子在这方面的有效性。

DESCRIPTION (Provided by the applicant) Abstract: Engineering Effective Revascularization Technologies for Ischemia in Disease States Chronic myocardial ischemia disease affects more than 27 milion patients in the United States and is the leading cause of morbidity and mortality in developed countries. Peripheral ischemic is even more prevalent being present in 12-20% of the population aged 65 and older in the US. Ischemic disease most often occurs as a result of arterial narrowing due to long-standing atherosclerotic disease processes. This arterial remodeling leads to a reduction in blood flow and, ultimately, causes organ dysfunction and failure. Current therapies for treating ischemia include the use of percutaneous interventions to physically open the artery or surgical methods to reroute blood flow to the poorly perfused tissue. These methods have significant limitations and eventually fail in the long-term. The most effective means to treat ischemic disease would be to revascularize the tissue by stimulating the development of native vasculature. Many studies have been done to attempt to use growth factors, growth factor genes and implanted cells to facilitate revascularization of ischemic tissues. While these treatments have been effective in experimental models, clinical trials have shown them to have limited efficacy in treating human disease. This proposal aims to understand why growth factor based therapies have failed to treat ischemia in patients and seeks to create novel therapeutics to increase growth factor effectiveness in this context. Our fundamental hypothesis is that the reason these therapies have failed is that tissues with long standing disease and exhausted compensatory mechanisms are unable to respond with appropriate growth factor signaling. Through basic studies on diseased cells and tissues, we will perform a detailed analysis of signaling pathways to identify the reasons for the ineffective growth factor signaling. We recently developed novel techniques allowing the replacement of missing receptors and co-receptors on the cell surface. Using these and other innovative methods we will pursue novel therapeutic drug formulations that can be utilized as co-treatments to allow growth factors to be efficacious in the presence of clinical disease. We will test these new treatments in clinically relevant animal models of peripheral and myocardial ischemia. Together, the studies performed and the tools developed will increase our understanding of how tissues become resistant to revascularization therapies and may lead to more effective treatments for this widespread and debilitating disease. Public Health Relevance: Chronic myocardial ischemia disease affects about 27 million patients in the United States and is the leading cause of morbidity and mortality in developed countries. Peripheral ischemic is even more prevalent being present in 12-20% of the population aged 65 and older in the US. This proposal seeks to understand why growth factor based therapies have failed to treat ischemia in patients and seeks to create novel therapeutics to increase growth factor effectiveness in this context.