Engineering Effective Revascularization Strategies for Ischemia in Disease States

针对疾病状态下的缺血设计有效的血运重建策略

• 批准号: 8146779
• 负责人: Aaron Blair Baker
• 金额: $ 231.45万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8146779
• 关键词: Affect; Animal Model; Arteries; Blood flow; Cell surface; Cells; Chronic; Clinical; Clinical Trials; Developed Countries; Development; Disease; Drug Formulations; Effectiveness; Engineering; Experimental Models; Failure; Functional disorder; Growth Factor; Growth Factor Gene; Implant; Intervention; Ischemia; Lead; Methods; Morbidity - disease rate; Myocardial Ischemia; Operative Surgical Procedures; Organ; Patients; Peripheral; Population; Process; Resistance; Signal Pathway; Signal Transduction; Techniques; Technology; Testing; Tissues; United States; abstracting; aged; arterial remodeling; base; clinically relevant; effective therapy; exhaust; human disease; innovation; mortality; novel; novel therapeutics; public health relevance; receptor; tool

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.

描述（由申请人提供） 摘要：针对疾病状态下的缺血设计有效的血运重建技术在美国，慢性心肌缺血疾病影响着超过 2700 万患者，是发达国家发病和死亡的主要原因。在美国，12-20% 的 65 岁及以上人口中，外周缺血更为普遍。缺血性疾病最常因长期动脉粥样硬化性疾病过程导致动脉狭窄而发生。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。目前治疗缺血的疗法包括使用经皮干预措施物理打开动脉或通过手术方法将血流重新引导至灌注不良的组织。这些方法有很大的局限性，从长远来看最终会失败。治疗缺血性疾病最有效的方法是通过刺激天然脉管系统的发育来使组织血运重建。已经进行了许多研究尝试使用生长因子、生长因子基因和植入细胞来促进缺血组织的血运重建。虽然这些疗法在实验模型中有效，但临床试验表明它们在治疗人类疾病方面的功效有限。该提案旨在了解为什么基于生长因子的疗法无法治疗患者的缺血，并寻求创造新的疗法来提高生长因子在这种情况下的有效性。我们的基本假设是，这些疗法失败的原因是患有长期疾病且补偿机制耗尽的组织无法对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分析，找出生长因子信号传导无效的原因。我们最近开发了新技术，可以替换细胞表面缺失的受体和共受体。利用这些和其他创新方法，我们将寻求可用作辅助治疗的新型治疗药物制剂，以使生长因子在临床疾病存在时发挥作用。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疗法。总之，所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，并可能为这种广泛且使人衰弱的疾病带来更有效的治疗。 公共健康相关性：慢性心肌缺血疾病影响着美国约 2700 万患者，是发达国家发病和死亡的主要原因。在美国，12-20% 的 65 岁及以上人口中，外周缺血更为普遍。该提案旨在了解为什么基于生长因子的疗法无法治疗患者的缺血，并寻求创造新的疗法来提高生长因子在这种情况下的有效性。