OVEREXPRESSION OF ENOS IN CRITICAL LIMB ISCHEMIA

ENOS 在严重肢体缺血中的过度表达

• 批准号: 6837663
• 负责人: Louis Michael Messina
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837663
• 关键词: aging; angiogenesis; angiography; cardiovascular disorder; collateral circulation; diabetes mellitus; disease /disorder model; enzyme activity; gene delivery system; hypercholesterolemia; immunocytochemistry; inflammation; ischemia; laboratory rat; limbs; nitric oxide synthase; perfusion; smoking; stem cells; tobacco abuse; transfection

DESCRIPTION (provided by applicant): Despite advances in the surgical and catheter-based treatments for critical limb ischemia (CLI), 150,000 patients require lower limb amputation in the United States annually. Believing that an effective molecular therapy would have a significant clinical impact on the disability and limb loss rates in these patients, this study looks specifically at the role of endothelial nitric oxide synthase (eNOS) in collateral artery development (arteriogenesis). Because such development can reverse CLI, our central hypothesis maintains that the overexpression of eNOS will induce the ordered and sustainable development of collateral arteries in a way that will reverse CLI. Specifically, this research proposal aims 1) to identify the optimal gene transfer condition in a rat hind limb mode of ischemia; 2) to examine whether these eNOS gene transfer techniques can also reverse CLI clinically relevant animal models of diabetes, advanced age and hypercholesterolemia, and cigarette smoking; and 3) to characterize the molecular mechanisms by which eNOS overexpression increases arteriogenesis. To accomplish these aims, our research plan employs novel gene delivery techniques and sites of delivery. In particular, a unique method of intra-arterial gene transfer under vascular isolation that results in highly efficient and localized transgene expression will be used for gene transfer and laser Doppler perfusion imaging to measure dermal blood flow will facilitate the accomplishment of the above aims. Understanding the mechanisms by which eNOS exerts its powerful effects on arteriogenesis should provide additional insight into the fundamental mechanisms regulating arteriogenesis, and therefore open new therapeutic approaches for the treatment of CLI and other vascular diseases.

描述（由申请人提供）： 尽管针对关键肢体缺血（CLI）的手术和基于导管的治疗方法在美国每年需要下肢截肢。认为有效的分子疗法将对这些患者的残疾和肢体损​​失率产生重大临床影响，该研究专门研究内皮一氧化氮合酶（ENOS）在侧支动脉发育（动脉生成）中的作用。由于这种发展可以逆转CLI，因此我们的中心假设认为，eNOS的过表达将诱导抵押动脉的有序和可持续发展，以逆转CLI。具体而言，该研究提案的目的是1）在缺血的大鼠后肢模式下确定最佳基因转移条件； 2）检查这些eNOS基因转移技术是否还可以逆转CLI临床上相关的糖尿病动物模型，高龄和高胆固醇血症以及吸烟； 3）表征eNOS过表达增加动脉生成的分子机制。为了实现这些目标，我们的研究计划采用了新颖的基因输送技术和分娩地点。特别地，在血管分离下，一种独特的动脉内基因转移方法将用于高效和局部的转基因表达，用于基因转移，激光多普勒灌注成像以测量真皮血流，将促进上述目标的实现。了解eNOS对动脉生成作用的强大作用的机制应提供对调节动脉生成的基本机制的更多见解，从而为治疗CLI和其他血管疾病的治疗开放新的治疗方法。