Engineering Blood Vessels to Resist Atherosclerosis

描述（由申请人提供）：动脉粥样硬化导致心脏病发作、中风和周围血管疾病，是血管壁内发展的疾病过程的结果。这一建议旨在开发基因疗法，将其传递到血管壁，以阻止推动动脉粥样硬化进展的生物过程。最终，通过在人类血管组织中表达抗动脉粥样硬化转基因，这种方法可能产生无限期无病的血管，因为它们对导致动脉粥样硬化的潜在生物过程具有抵抗力。这是一个雄心勃勃的目标，其中的工作肯定会超出目前的建议。然而，目前的建议建立在首席研究员实验室几年的进展基础上，并提出了动脉粥样硬化基因治疗的下一步关键步骤。

DESCRIPTION (provided by applicant): Atherosclerosis causes heart attacks, strokes, and peripheral vascular disease, and is a consequence of disease processes that develop within the blood vessel wall. This proposal seeks to develop gene therapy, delivered to the blood vessel wall, that prevents the biological processes that drive the progression of atherosclerosis. Eventually, by expressing anti-atherosclerotic transgenes in human vascular tissue, this approach may yield blood vessels that remain disease-free indefinitely because they are resistant to the underlying biological processes that cause atherosclerosis. This is an ambitious objective, including work that is certain to extend beyond the current proposal. However, the current proposal builds on several years of progress in the laboratory of the Principal Investigator and sets forth the next critical steps towards gene therapy for atherosclerosis. There are three specific aims. The first specific aim will test gene-therapy strategies that prevent atherosclerosis by increasing lipid transport out of the vessel wall or by decreasing vascular inflammation. The second aim includes experiments that will reveal the duration of transgene expression that can be achieved in vascular tissue using helper-dependent adenoviral vectors. Other experiments will test strategies for increasing transgene expression from these vectors. The third aim will test the hypothesis that helper- dependent adenoviral vectors will provide durable transgene expression with minimal associated inflammation in vein grafts. Success in these aims will represent significant progress towards development of clinically useful vascular gene therapy. PUBLIC HEALTH RELEVANCE: The three current therapies for atherosclerosis-drugs, angioplasty, and bypass surgery-have not eliminated death and disability associated with atherosclerosis. Patients receiving one or even all three of these therapies continue to be at risk for heart attacks, strokes, and limb loss. Development and clinical application of methods and tools to genetically engineer blood vessels so that they do not develop atherosclerosis-and therefore never become narrowed or clogged-would have a major impact on the morbidity, mortality, and health-care costs of cardiovascular disease.