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（申请人提供） 摘要：在疾病状态下，慢性心肌缺血疾病的缺血技术有效的血运重建技术影响了美国的270万名患者，并且是发达国家发病率和死亡率的主要原因。在美国，在65岁及以上年龄较大的人口中，外围缺血更为普遍。缺血性疾病最常是由于长期因动脉粥样硬化过程而导致的动脉狭窄而发生的。这种动脉重塑导致血流减少，并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在物理上打开动脉或手术方法，以将血液流动到灌注不良的组织。这些方法具有重大的局限性，并最终从长远来看失败。治疗缺血性疾病的最有效方法是通过刺激天然脉管系统的发展来血运组织。已经进行了许多研究，以尝试使用生长因子，生长因子基因和植入细胞来促进缺血组织的血运重建。尽管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疗效有限。该建议旨在了解为什么基于生长因子的疗法未能治疗患者缺血，并试图在这种情况下创建新型的治疗疗法以提高生长因素的有效性。我们的基本假设是，这些疗法失败的原因是，患有长期疾病和耗尽的补偿机制的组织无法以适当的生长因子信号传导做出反应。通过对患病细胞和组织的基础研究，我们将对信号通路进行详细分析，以确定无效生长因子信号传导的原因。我们最近开发了新型技术，允许在细胞表面替换缺失的受体和受体受体。使用这些和其他创新方法，我们将采用新型的治疗药物制剂，可用于共同处理，以使生长因子在存在临床疾病的情况下具有有效性。我们将在外周和心肌缺血的临床相关动物模型中测试这些新疗法。共同进行的研究和开发的工具将增加我们对组织如何抗血运重建疗法的理解，并可能导致对这种广泛和使人衰弱的疾病的更有效治疗。 公共卫生相关性：慢性心肌缺血疾病在美国影响约2700万患者，是发达国家发病率和死亡率的主要原因。在美国，在65岁及以上年龄较大的人口中，外围缺血更为普遍。该建议试图理解为什么基于生长因子的疗法未能治疗患者缺血，并试图在这种情况下创建新型的治疗疗法以提高生长因子的有效性。