The Role of VDR in PTH and Vitamin D3(D3) Synergy

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DESCRIPTION (provided by applicant): The objective of this K08 Mentored Clinician Scientist Award is to provide the principal investigator Tara Aghaloo, DDS, MD, with the training and experience to develop as an independent investigator to complement her clinical training in oral and maxillofacial surgery. Dr. Aghaloo's training will be under the guidance of her mentor Dr. Sotirios Tetradis and co-mentor Dr. Karen Lyons. Dr. Aghaloo's goal is to pursue an academic career and establish herself as an independent dentist scientist, conducting molecular biology research, mentoring students and residents, and practicing oral and maxillofacial surgery. Bone is a dynamic tissue important for calcium homeostasis, stature and internal organ protection. Bone metabolism is a critical parameter in dental health. Bone healing and regeneration have important implications in implant osseointegration, extraction socket healing, critical-sized oral and maxillofacial defects, and orthopedic reconstruction. Treatments to enhance bone regeneration improve surgical predictability and success, and prevent alveolar bone loss. Our rationale is that understanding the molecular mechanism of bone metabolism will help design anabolic therapies for local and systemic bone regeneration, and will greatly impact medicine and dentistry. Parathyroid hormone (PTH) and 1, 25-dihydroxyvitamin D3 (D3) have significant anabolic effects on bone, yet we do not understand the molecular mediators of these effects. Preliminary studies reveal that PTH treatment rapidly and transiently induces VDR in vitro and in vivo, respectively. In vitro, PTH's regulation of VDR gene expression signals through the cAMP-PKA pathway. We also found a synergy between PTH and D3 in their induction of the osteocalcin promoter. We hypothesize that a functional VDR is critical for the synergistic effect of PTH and D3 on osteoblast differentiation and function. To test our hypothesis, we propose three specific aims. (1) To characterize PTH-induced VDR gene expression in vivo; (2) To determine the importance of VDR regulation for the PTH effects on osteoblastic function; and (3) To identify genes synergistically upregulated by PTH and D3. These studies will help understand the mechanisms of PTH and D3 synergy through VDR and their effects on osteoblastic differentiation and function.