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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-M (04))
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Tondravi, Mehrdad M
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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Wang, Meina; Nasiri, Ali R; Broadus, Arthur E et al. (2015) Periosteal PTHrP Regulates Cortical Bone Remodeling During Fracture Healing. Bone 81:104-111
Wang, Meina; Nasiri, Ali; VanHouten, Joshua N et al. (2014) The remarkable migration of the medial collateral ligament. J Anat 224:490-8
Wang, Meina; VanHouten, Joshua N; Nasiri, Ali R et al. (2014) Periosteal PTHrP regulates cortical bone modeling during linear growth in mice. J Anat 225:71-82
Wang, Meina; VanHouten, Joshua N; Nasiri, Ali R et al. (2013) PTHrP regulates the modeling of cortical bone surfaces at fibrous insertion sites during growth. J Bone Miner Res 28:598-607
Karaplis, Andrew C; Bai, Xiuying; Falet, Jean-Pierre et al. (2012) Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in hyp mice. Endocrinology 153:5906-17
Macica, Carolyn; Liang, Guoying; Nasiri, Ali et al. (2011) Genetic evidence of the regulatory role of parathyroid hormone-related protein in articular chondrocyte maintenance in an experimental mouse model. Arthritis Rheum 63:3333-43
Liang, Guoying; Katz, Lee D; Insogna, Karl L et al. (2009) Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif Tissue Int 85:235-46
Chen, Xuesong; Macica, Carolyn M; Nasiri, Ali et al. (2008) Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. Arthritis Rheum 58:3788-97
Chen, Xuesong; Macica, Carolyn; Nasiri, Ali et al. (2007) Mechanical regulation of PTHrP expression in entheses. Bone 41:752-9
Liang, Guoying; Cline, Gary W; Macica, Carolyn M (2007) IGF-1 stimulates de novo fatty acid biosynthesis by Schwann cells during myelination. Glia 55:632-41

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