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.
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