The general working hypothesis of this proposal is that regulation of L-type voltage-sensitive calcium channels (L-VSCCs) is an important aspect of PTHrP action in several of its target tissues. We propose to study this question in two aims, the first involving PTHrP regulatory effects in the CNS and the second exploring PTHrP as a candidate mediator of the effects of mechanical force on bone. ? ? Specific Aim I. It is our hypothesis that PTHrP serves as the effector molecule in a feedback loop that protects against excitotoxic damage in the CNS by keeping L-VSCC Ca2+ influx in check. There are four sub-aims: 1) to create and/or use a number of mouse models that will enable study of this question in vivo, 2) to study the capacity of PTHrP to oppose ischemic/hypoxic excitotoxicity, 3) to determine if PTHrP might be responsible for the phenomenon of 'tolerance"""""""" induced by pre-conditioning with a mild excitotoxic challenge and 4) to study the mechanism of the cell survival effects of PTHrP. Sub-aims 2,3, and 4 each comprise experiments in vivo as well as in vitro. ? ? Specific Aim II. We propose to explore the possible role of PTHrP and mediating the anabolic effects of mechanical force on bone. This is a new initiative. Experimentally, this aim reduces to a proximal end, designed to examine the effects of mechanical force on PTHrP expression/secretion by osteoblast-like cells, and a distal end, designed to explore PTHrP regulation of osteoblastic channel and anabolic function. We will use UMR lines as surrogates for osteoblasts/osteocytes and variations in tonicity as a surrogate for mechanical force.
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