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

描述（由申请人提供）：K08 指导临床医生科学家奖的目的是为首席研究员 Tara Aghaloo（DDS、MD）提供培训和经验，使其成为一名独立研究者，以补充她在口腔颌面外科方面的临床培训。 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。 Aghaloo 博士的目标是追求学术生涯，并成为一名独立的牙医科学家，进行分子生物学研究，指导学生和住院医生，并从事口腔颌面外科手术。骨骼是一种动态组织，对于钙稳态、身高和内脏器官保护非常重要。骨代谢是牙齿健康的关键参数。骨愈合和再生对于种植体骨整合、拔牙槽愈合、临界尺寸的口腔颌面部缺损以及骨科重建具有重要意义。增强骨再生的治疗可提高手术的可预测性和成功率，并防止牙槽骨丢失。我们的理由是，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) 对骨骼具有显着的合成代谢作用，但我们不了解这些作用的分子介质。初步研究表明，PTH 治疗分别在体外和体内快速且短暂地诱导 VDR。在体外，PTH通过cAMP-PKA途径调节VDR基因表达信号。我们还发现 PTH 和 D3 在诱导骨钙素启动子方面具有协同作用。我们假设功能性 VDR 对于 PTH 和 D3 对成骨细胞分化和功能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) 表征PTH诱导的VDR基因体内表达； (2) 确定VDR调节对于PTH对成骨细胞功能影响的重要性； (3)鉴定PTH和D3协同上调的基因。这些研究将有助于了解 PTH 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.