A New Regulator of Trabecular Bone Formation

项目概述/摘要影响骨骼和关节的肌肉骨骼疾病是一个日益严重的健康问题。骨质疏松症影响着美国超过1000万人。此外，每年因骨折就诊的急诊人数超过300万。由于我们治疗和预防这些疾病的能力仍然非常初级，阐明调节骨形成的机制对于理解骨疾病的病理变化和开发靶向治疗来增加骨形成至关重要。先前的研究结果发现了一组g蛋白偶联受体，它们在Gs-GPCR信号通路激活后在成骨细胞中高度表达。其中一种受体，GPR116，是一种孤儿粘附GPCR，在骨形成中没有被发现的作用。初步研究表明GPR116可以调控小梁骨形成。本提案的总体目标是通过系统的方法确定GPR116在骨骼中的作用，具体目标有三个：1)识别由GPR116激活的信号通路；2)通过组织特异性敲除小鼠模型确定GPR116在成骨细胞中的生理作用；3)利用人诱导多能干细胞模型系统确定GPR116是否调节软骨或骨的形成。这些研究的成功完成将确定GPR116在调节小梁骨形成中的作用，并有助于我们了解粘附gpcr的功能。研究结果将为未来研究GPR116如何调节骨组织形成、肿瘤转移或异位骨形成建立强有力的框架。拟议的研究是一个协调的职业发展计划的一部分，以准备候选人成为一个杰出的，独立的医师-科学家。在奖励结束时，候选人将使用本研究的结果和试剂申请独立研究者奖励，如NIH R01资助。

DESCRIPTION (provided by applicant): Project Summary/Abstract Musculoskeletal disorders affecting the bones and joints are a growing health problem. Osteoporosis affects over 10 million people in the United States. In addition, bone fractures result in over 3 million emergency department visits a year. Since our ability to treat and prevent these diseases is still very rudimentary, elucidating the mechanisms that regulate bone formation is crucial for understanding the pathologic changes in bone diseases and for developing targeted treatments to increase bone formation. Prior results identified a group of G-protein coupled receptors that are highly expressed in osteoblasts after activation of the Gs-GPCR signaling pathway. One of these receptors, GPR116, is an orphan adhesion GPCR with no previously identified role in bone formation. Preliminary studies indicate that GPR116 can regulate trabecular bone formation. The overall objective of this proposal is to define the roles of GPR116 in the skeleton using a systematic approach in three specific aims: 1) identify the signaling pathways activated by GPR116; 2) determine the physiologic role of GPR116 in osteoblasts using a tissue-specific knockout mouse model; and 3) determine if GPR116 regulates the formation of cartilage or bone using a human induced pluripotent stem (iPS) cell model system. Successful completion of these studies will identify the roles of GPR116 in regulating trabecular bone formation and contribute to our understanding about the function of adhesion GPCRs. The results will establish a strong framework for future studies including how GPR116 regulates skeletal tissue formation, tumor metastasis, or ectopic bone formation. The proposed research is part of a coordinated career development plan to prepare the candidate to be an outstanding, independent physician-scientist. At the end of this award, the results and reagents from this study will be used by the candidate to apply for an independent investigator award such as the NIH R01 grant.