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

描述(由申请者提供)：本次K08临床指导科学家奖的目标是为首席研究员Tara Aghaloo，DDS，MD，提供培训和经验，以发展为一名独立的研究员，以补充她在口腔和颌面外科的临床培训。Aghaloo博士的培训将在她的导师Sotirios Tetradis博士和共同导师Karen Lyons博士的指导下进行。阿加鲁博士的目标是追求学术生涯，成为一名独立的牙医科学家，从事分子生物学研究，指导学生和住院医生，并实践口腔和颌面外科。骨骼是一种动态组织，对钙平衡、身高和内部器官保护都很重要。骨代谢是影响牙齿健康的重要参数。骨的愈合和再生对种植体的骨整合、拔牙槽骨愈合、口腔颌面部的临界大小缺损和矫形重建具有重要的意义。促进骨再生的治疗提高了手术的预见性和成功率，并防止了牙槽骨丢失。我们的理论基础是，了解骨代谢的分子机制将有助于设计局部和全身骨再生的合成代谢疗法，并将极大地影响医学和牙科。甲状旁腺激素(PTH)和1，25-二羟基维生素D3(D3)对骨骼有显著的合成代谢作用，但这些作用的分子介体尚不清楚。初步研究表明，甲状旁腺素处理在体外和体内分别快速和瞬时地诱导VDR。在体外，PTH通过cAMP-PKA途径调节VDR基因的表达。我们还发现甲状旁腺素和D3在诱导骨钙素启动子方面具有协同作用。我们推测，功能性的VDR对于PTH和D3在成骨细胞分化和功能上的协同作用至关重要。为了检验我们的假设，我们提出了三个具体目标。(1)研究甲状旁腺激素(PTH)诱导的VDR基因在体内的表达；(2)确定VDR调控在PTH对成骨细胞功能影响中的重要性；(3)鉴定PTH和D3协同上调的基因。这些研究将有助于了解甲状旁腺激素和D3通过VDR协同作用的机制及其对成骨细胞分化和功能的影响。

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.