Limb Neurovascular Control and Aging

描述(由申请人提供)：应聘者的短期目标是获得高级研究培训，以显着扩大其研究能力。候选者的长期目标是确定人类神经循环控制中与年龄相关的有害变化的潜在机制。候选人具有执行生物医学重大衰老研究的既定能力和承诺，并已成功获得外部资金(个人NRSA)。指导团队的成员在进行高质量的外部支持的衰老研究和培训调查人员方面有很强的历史。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调查人员的发展至关重要的各个方面，如正式课堂教学培训、使用现代实验技术的培训、介绍和传播研究结果、直接指导以及与现有调查人员的互动。这项建议中概述的研究将利用直接记录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和肢体血流量的直接记录，来综合研究在人类中枢低血容量性应激期间与年龄和肢体相关的外周血流调节差异的机制。将检验以下假设：1)静息和中枢性低血容量引起的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的增加会在老年人的手臂和腿部引起迟钝的血管收缩反应。2)[NE]i在青壮年静息和中枢性血容量减少时，上臂大于腿部。此外，与年轻人相比，在休息和中枢性血容量减少时，老年人的手臂和腿部[NE]i都更大。3)与年龄和肢体相关的[NE]i差异的机制涉及突触去甲肾上腺素水平的调节器(摄取1)，而不是突触前α-2肾上腺素能调节NE的释放。

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.