Limb Neurovascular Control and Aging

描述（由申请人提供）：候选人的短期目标是获得高级研究培训，以显着扩展其研究能力。候选人的长期目标是确定人类神经循环控制中有害的年龄相关变化的机制。候选人有能力和承诺进行生物医学上重要的衰老研究，并已成功获得校外资助（个人NRSA）。指导团队的成员在执行高质量的外部支持的老龄化研究和培训调查人员方面有着悠久的历史。宾夕法尼亚州立医学院（主办机构）的资源非常好。研究培训计划涉及对未来独立研究者发展至关重要的方面，如正式的课堂培训、现代实验技术的使用培训、研究成果的展示和传播、直接指导以及与已有研究者的互动。本提案中概述的研究将利用手臂和腿部肌肉交感神经活动（MSNA）、骨骼肌间质去甲肾上腺素浓度[NE]i和肢体血流的直接记录，综合研究人类中心性低血容量应激期间外周血流量调节中年龄和肢体相关差异的机制。以下假设将被检验：1)静息和中枢性低血容量诱导的MSNA增加在老年人的手臂和腿部是相似的。然而，与年轻人相比，中枢性低血容量时肢体MSNA的增加会导致老年人手臂和腿部血管收缩反应减弱。2) [NE]年轻成人在休息时和中枢性低血容量时，手臂比腿部更大。此外，与年轻人相比，老年人在休息和中枢性低血容量时手臂和腿部[NE]i更大。3)年龄和肢体相关[NE]i差异的机制涉及突触去甲肾上腺素水平的调节（摄取1），而不是突触前α -2肾上腺素能调节的NE释放。

DESCRIPTION (provided by applicant): The candidate's short-term goal is to obtain advanced research training to significantly expand his research capabilities. The long-term goal of the candidate is to determine the mechanisms underlying detrimental age-associated changes in neurocirculatory control in humans. The candidate has an established ability and commitment to performing biomedically significant aging research and has successfully obtained extramural funding (Individual NRSA). Members of the mentoring team have a strong history of performing high quality extramurally-supported aging research and of training investigators. The resources at the Penn State College of Medicine (host institution) are excellent. The research training plan involves aspects critical to the development of future independent investigators such as formal classwork training, training in the use of modern experimental techniques, presenting and disseminating research findings, direct mentoring, and interacting with established investigators. Studies outlined in this proposal will utilize direct recordings of arm and leg muscle sympathetic nerve activity (MSNA), interstitial norepinephrine concentrations [NE]i in skeletal muscle, and limb blood flow to integratively examine mechanisms underlying age- and limb-related differences in peripheral blood flow regulation during central hypovolemic stress in humans. The following hypotheses will be tested: 1) resting and central hypovolemia-induced increases in MSNA are similar in the arm and leg of older adults. However, increases in limb MSNA during central hypovolemia elicit blunted vasoconstrictor responses in both the arm and leg of older compared to younger adults. 2) [NE]i is greater in the arm than the leg at rest and during central hypovolemia in young adults. Moreover, both arm and leg [NE]i are greater in older adults at rest and during central hypovolemia compared to young adults. 3) The mechanisms underlying age- and limb-related differences in [NE]i involve modulators of synaptic norepinephrine levels (uptake 1), but not presynaptic alpha-2 adrenergic modulation of NE release.