A New Regulator of Trabecular Bone Formation

描述（由申请人提供）：项目摘要/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。骨质疏松症在美国影响超过1000万人。此外，骨折导致每年超过300万次急诊。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以增加骨形成至关重要。先前的结果鉴定了一组G蛋白偶联受体，其在Gs-GPCR信号通路激活后在成骨细胞中高度表达。这些受体之一，GPR 116，是一种孤儿粘附GPCR，以前没有发现在骨形成中的作用。初步研究表明，GPR 116可以调节骨小梁形成。本研究的总体目标是采用系统的方法确定GPR 116在骨骼中的作用，具体目标有三个：1）鉴定GPR 116激活的信号通路; 2）使用组织特异性敲除小鼠模型确定GPR 116在成骨细胞中的生理作用;和3）使用人诱导多能干（iPS）细胞模型系统确定GPR 116是否调节软骨或骨的形成。这些研究的成功完成将确定GPR 116在调节骨小梁形成中的作用，并有助于我们对粘附GPCR功能的理解。这些结果将为未来的研究建立一个强有力的框架，包括GPR 116如何调节骨骼组织形成，肿瘤转移或异位骨形成。拟议的研究是一个协调的职业发展计划的一部分，准备候选人是一个杰出的，独立的医生科学家。在该奖项结束时，候选人将使用本研究的结果和试剂申请独立研究者奖，如NIH R 01补助金。

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.