Vascular Function with Aging, Viral Gene Therapy and Exercise Training

血管功能与衰老、病毒基因治疗和运动训练

• 批准号: 7530464
• 负责人: Brad J Behnke
• 金额: $ 11.28万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7530464
• 关键词: Abdomen; Address; Adenoviruses; Adipose tissue; Adrenergic Agents; Aerobic; Affect; Age; Aging; Animals; Architecture; Arginine; Attenuated; Beds; Biological Availability; Blood Vessels; Blood flow; Cardiac; Cardiac Output; Cardiovascular system; Characteristics; Chronic; Chronic Disease; Condition; Detection; Development; Elderly; Endothelium; Exercise; Foundations; Functional disorder; Funding; Future; GTP Cyclohydrolase; Goals; Human; Individual; Invasive; Life Style; Link; Maintenance; Messenger RNA; Microcirculation; Modeling; Molecular; Muscle; Nitric Oxide Synthase; Numbers; Oxygen; Oxygen Consumption; Perforating Artery; Peripheral; Physical Capacity; Physical activity; Play; Population; Principal Investigator; Proteins; Protocols documentation; Range; Rat-1; Rattus; Research; Research Personnel; Research Priority; Research Proposals; Resistance; Resolution; Risk; Role; Skeletal Muscle; Solid; State Medicine; Structure; Techniques; Testing; Thinking; Tissues; Training; United States; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vasodilation; Viral; Work; adrenergic; age effect; age related; aged; analog; arginase; base; career; conditioning; design; frailty; gene therapy; hemodynamics; human very old age (85+); insight; journal article; juvenile animal; mRNA Expression; middle age; novel; oxygen transport; programs; protein expression; research study; senescence; skills; tetrahydrobiopterin; vasoconstriction

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.

描述（由申请人提供）：身体能力和肌肉功能随着年龄的增长而下降。与年龄相关的肌肉血流量及其在骨骼肌内和之间的血管内分布的减少被认为在机制上与老年人的肌肉功能障碍有关。然而，迄今为止，年轻和老年骨骼肌内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与年龄相关，因此该组织床中血管反应性的改变可能会影响老年人群的全身血流动力学和骨骼肌血流。我计划检验一个广泛的假设，即衰老会导致微循环功能障碍（结构性和功能性），从而损害氧气输送，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，该模型是一种广泛接受的人类状况模拟模型，其主要优点是允许进行非常侵入性的研究。该应用程序的总体目标是为我提供新的补充技能，使我成为一名独立研究人员，并为我开展科学职业生涯奠定基础。在这方面，每个具体目标将使我掌握一项新技术，以解决年轻、中年和老年大鼠的以下问题：1）阐明骨骼的结构（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） 通过分离微血管技术研究肌肉和脂肪组织阻力血管，2) 检查长期运动训练引起的骨骼肌脉管系统的变化，3) 通过腺病毒基因治疗短暂改变 eNOS、VEGF 或 GTP 环化水解酶 mRNA 和蛋白表达，以及 4) 确定脂肪组织血管反应性随年龄的变化是否可能有助于减少 运动时骨骼肌的血流量。制定有效策略来减轻衰老对身体能力的有害影响取决于解决该人群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开启独立职业生涯提供基础。