Vascular Function with Aging, Viral Gene Therapy and Exercise Training

描述（由申请人提供）：体能和肌肉功能随着年龄的增长而下降。骨骼肌内和骨骼肌之间的肌肉血流量及其血管内分布的减少与老年人的肌肉功能障碍有关。然而，到目前为止，年轻和老年骨骼肌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存在与年龄相关的增加，因此该组织床中的血管反应性改变可能影响老年人群中的全身血液动力学和骨骼肌血流。我计划测试一个广泛的假设，即衰老诱导微循环功能障碍（结构和功能），损害氧气运输，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，这是一个被广泛接受的模拟人类状况的主要优势，允许非常侵入性的研究。这个应用程序的总体目标是为我提供新的和互补的技能，成为一个独立的研究人员，并提供一个基础，启动我的科学生涯。在这方面，每一个具体的目标将使我掌握一种新的技术，以解决以下在年轻，中年和老年大鼠：1）阐明结构（例如，血管几何形状），功能（例如，用四氢生物蝶呤或L-精氨酸孵育的内皮依赖性血管舒张），和分子特征（例如，eNOS mRNA和蛋白质表达），2）检查由长时间运动训练引起的骨骼肌血管系统的改变，3）通过腺病毒基因治疗短暂改变eNOS、VEGF或GTP环化水解酶mRNA和蛋白质表达，（4）确定脂肪组织血管反应性随年龄的变化是否会导致运动时骨骼肌血流量的减少。发展有效的策略，以减轻老化对身体能力的有害影响，是取决于在这个人群中的肌肉功能障碍的机制基础的决议。在这方面，这些具体目标旨在解决衰老个体身体限制的几个重要潜在机制，并为未来的研究和资助提供基础，以启动独立的职业生涯。

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.