Vascular Function with Aging, Viral Gene Therapy and Exercise Training

描述(申请人提供)：体能和肌肉功能随着年龄的增长而降低。与年龄相关的肌肉血流量减少及其在骨骼肌内部和之间的血管内分布被认为与老年人肌肉功能障碍有机械联系。然而，到目前为止，年轻和老年骨骼肌之间的关键结构和功能关系仍然不清楚。此外，由于脂肪组织的百分比随着年龄的增长而增加，这种组织床中血管反应性的改变可能会影响老年人口的全身血流动力学和骨骼肌血流量。我计划测试一个广泛的假设，即衰老会导致微循环功能障碍(结构和功能)，从而损害氧气运输，而运动训练可以减轻这种微循环功能障碍。这项工作将利用衰老的大鼠模型，这是一种被广泛接受的与人类状况类似的模型，其主要优势是允许进行非常侵入性的研究。这个应用程序的总体目标是为我提供新的和补充的技能，使我成为一名独立的研究人员，并为我开始科学生涯提供基础。在这方面，每个特定的目标将使我能够掌握一种新的技术来解决年轻、中年和老年大鼠的下列问题：1)通过分离微血管技术阐明骨骼肌和脂肪组织阻力血管的结构(例如，血管几何形状)、功能(例如，四氢生物蝶呤或L-精氨酸温育的内皮依赖性血管扩张)和分子特征(例如，enos mRNA和蛋白表达)；2)研究长期运动训练引起的骨骼肌血管系统的变化；3)通过腺病毒基因治疗瞬时改变eNOS、血管内皮生长因子或GTP环水解酶的基因和蛋白表达。4)确定运动中脂肪组织血管反应性随年龄的变化是否与骨骼肌血流量减少有关。开发有效的策略来减轻衰老对体能的有害影响取决于该人群肌肉功能障碍的机制基础的解决。在这方面，这些具体目标寻求解决老年人身体局限性的几个重要潜在机制，并为未来的研究和启动独立职业生涯的资金提供基础。

DESCRIPTION (provided by applicant): Physical capacity and muscular function are reduced with aging. Age-associated reductions in muscle blood flow and its intravascular distribution within and between skeletal muscles is thought to be linked mechanistically to muscle dysfunction in older individuals. To date, however, key structural and functional relationships within young and aged skeletal muscle remain obscure. Furthermore, as there is an age- associated increase in the percentage of adipose tissue, altered vasoreactivity in this tissue bed may affect whole body hemodynamics and skeletal muscle blood flow in the aged population. I plan to test the broad hypothesis that aging induces microcirculatory dysfunction (both structural and functional) that impairs oxygen transport, and exercise training can attenuate this microcircular dysfunction. This work will utilize the rat model of aging that is a widely accepted analog of the human condition that has the major advantage of permitting very invasive studies. The overall goal of this application is to provide me with new and complementary skills to become an independent researcher, and provide a foundation to launch my scientific career. In this regard each specific aim will allow me to master a novel technique to address the following in young, middle-aged, and old rats: 1) Elucidate the structural (e.g., vascular geometry), functional (e.g., endothelium-dependent vasodilation with tetrahydrobiopterin or L-arginine incubation), and molecular characteristics (e.g., eNOS mRNA and protein expressions) of skeletal muscle and adipose tissue resistance vessels via the isolated microvessel technique, 2) Examine alterations in skeletal muscle vasculature resulting from prolonged exercise training, 3) Transiently alter eNOS, VEGF or GTP cyclohydrolase mRNA and protein expression via adenovirus gene therapy, and 4) Determine whether detremints in adipose tissue vasoreactivity with age may contrribute to reduce skeletal muscle blood flow during exercise. Development of effective strategies to attenuate the deleterious effects of aging on physical capacity is contingent upon resolution of the mechanistic bases for muscle dysfunction in this population. In this regard, these specific aims seek to address several important potential mechanisms for the physical limitations in senescent individuals, and provide the basis for future research and funding to initiate an independent career.