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）：