Osteoporosis is a major bone disorder that affects both men and women during aging. The pathogenesis is due largely to the increased osteoclast activity which is largely attributed to the increased generation of osteoclasts (osteoclastogenesis). Thus, understanding the cellular and molecular mechanisms in the regulation of osteoclastogenesis is of paramount importance in the battle against osteoporosis. Efforts proposed in this application are directed toward identifying novel targets for the treatment of osteoporosis. Accumulated preliminary data from both in vivo and in vitro studies, indicate a specific and important role of Ca2+/calmodulin dependent kinase II (CaMKII) in the regulation of osteoclastogenesis. Experimental aims are designed to address the hypothesis that CaMKII regulates osteoclastogenesis.
Specific aims to accomplish this are:
Specific Aim 1. Characterization of the roles of different CaMKII subtypes involved in osteoclastogenesis, i. Determine the cellular distribution of different CaMKII subtypes (apha and or gamma) in bone marrow, ii. Characterize CaMKII in cells from CaMKIIalpha mutant mice during osteoclastogenesis, iii. Characterize bone mineral density (BMD) changes in CaMKIIalpha mutant mice. iv. Further characterize the specificity of CaMKII alpha and or gamma in osteoclastogenesis by viral mediated gene transfer.
Specific Aim 2. Determine the molecular mechanisms of CaMKII regulation of osteoclastogenesis, i. Does CaMKII regulate RANKL signaling? ii. Identify the substrates of CamKII in RANKL signaling pathways, iii. Does CaMKII regulate macrophage fusion molecules? Elucidation of the molecular events responsible for CaMKII's involvement in osteoclastogenesis, will reveal detailed molecular mechanisms, which may provide new targets for designing rational therapeutic strategies to combat osteoporosis.
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