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

基本信息

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
项目类别：
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

项目摘要

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）：随着衰老而降低身体能力和肌肉功能。肌肉血流及其在骨骼肌内和之间的血管内分布的减少被认为与老年人的肌肉功能障碍有关。然而，迄今为止，年轻和老年骨骼肌肉内的关键结构和功能关系仍然晦涩难懂。此外，由于脂肪组织百分比的年龄增加，该组织床的血管反应性改变可能会影响年龄人群的全身血液动力学和骨骼肌血流。我计划检验一个广泛的假设，即衰老会诱导损害氧气传输的微循环功能障碍（结构性和功能性），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，这是人类状况的广泛接受的类似物，其具有允许非常侵入性研究的主要优势。该应用程序的总体目标是为我提供新的和互补的技能，以成为一名独立的研究人员，并为启动我的科学职业提供了基础。在这方面，每个具体目标都将使我能够掌握一种新颖的技术，以解决年轻，中年和老鼠中的以下技术：1）阐明结构性（例如血管几何形状），功能性（例如，依赖于内皮性的血管舒张，具有四氢无生物蛋白酶或l-芳香氨酸酯的剂量），以及l-氨基氨基氨基氨基酯的特征（E.G. e.g. e.g.MREACERIASS）（MRE）（MRE），MRESERISTIS（MR）肌肉和脂肪组织耐药性通过孤立的微血管技术，2）检查延长运动训练导致骨骼肌血管的变化，3）瞬时改变eNOS，VEGF或GTP环素酶mRNA和蛋白质通过腺病毒基因疗法的衰减量来减少掉落的vas vase液，并在运动过程中的骨骼肌血流。制定有效的策略来减轻衰老对身体能力的有害影响，取决于解决该人群中肌肉功能障碍的机械基础。在这方面，这些具体目标旨在解决衰老个体的身体局限性的几种重要机制，并为未来的研究和资金提供了启动独立职业的基础。