Vascular Function with Aging, Viral Gene Therapy and Exercise Training

描述（由申请人提供）：随着年龄的增长，身体能力和肌肉功能下降。与年龄相关的肌肉血流减少及其在骨骼肌内和骨骼肌之间的血管内分布被认为与老年人的肌肉功能障碍有机械联系。然而，到目前为止，年轻人和老年人骨骼肌之间的关键结构和功能关系仍然不清楚。此外，由于脂肪组织百分比随年龄增长而增加，这种组织层血管反应性的改变可能会影响老年人全身血流动力学和骨骼肌血流。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（结构性和功能性），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。这项工作将利用大鼠衰老模型，这是一种被广泛接受的人类状况的模拟，具有允许非常侵入性研究的主要优势。这个申请的总体目标是为我提供新的和互补的技能，成为一名独立的研究人员，并为我的科学事业奠定基础。在这方面，每一个具体的目标将使我掌握一种新的技术，以解决以下问题：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（如血管几何结构）、功能（如四氢生物蝶呤或l -精氨酸培养的内皮依赖性血管舒张）和分子特征（如eNOS mRNA和蛋白表达）；2)检查长时间运动训练导致的骨骼肌血管的改变；通过腺病毒基因治疗VEGF或GTP环水解酶mRNA和蛋白的表达。4)确定脂肪组织血管反应性随年龄的变化是否有助于减少运动时骨骼肌血流量。开发有效的策略来减轻衰老对身体能力的有害影响，取决于解决这一人群中肌肉功能障碍的机制基础。在这方面，这些具体目标旨在解决老年人身体限制的几个重要潜在机制，并为今后的研究和资助提供基础，以开始独立的职业生涯。

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.