A New Regulator of Trabecular Bone Formation

骨小梁形成的新调节器

• 批准号: 8099371
• 负责人: EDWARD C HSIAO
• 金额: $ 7.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8099371
• 关键词: Accident and Emergency department; Adhesions; Adult; Affect; Award; Biological Models; Blood; Bone Diseases; Bone Growth; Bone Regeneration; Bone Resorption; Cartilage; Cell model; Cells; Clinical Treatment; Cyclic AMP; Data; Defect; Development Plans; Disease; Dysplasia; ES Cell Line; Extracellular Matrix; Foundations; Fracture; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gene Expression; Goals; Grant; Health; Heterotopic Ossification; Hormones; Human; Immunohistochemistry; In Vitro; Joints; Knockout Mice; Ligands; Link; Metabolic Bone Diseases; Mus; Musculoskeletal Diseases; Neoplasm Metastasis; Nodule; Orphan; Osteoblasts; Osteogenesis; Osteoporosis; Pathologic; Pathway interactions; Phenotype; Phospholipase C; Physicians; Physiological; Process; Public Health; Reagent; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Skeleton; Specific qualifier value; Stem cells; System; Tissues; United States; United States National Institutes of Health; Visit; abstracting; adhesion receptor; base; bone; bone loss; bone mass; career; career development; effective therapy; human GPRC5C protein; human disease; improved; in vivo; in vivo Model; induced pluripotent stem cell; loss of function; mouse model; overexpression; pluripotency; prevent; receptor; repaired; skeletal disorder; skeletal tissue; substantia spongiosa; therapeutic target; tissue culture; tumor

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.

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。美国有1000多万人患有骨质疏松症。此外，每年有300多万人次因骨折而前往急诊科就诊。由于我们治疗和预防这些疾病的能力仍然非常初级，阐明骨形成的调节机制对于了解骨疾病的病理变化和开发靶向治疗以促进骨形成至关重要。以往的研究结果证实，在Gs-GPCR信号通路激活后，成骨细胞中高表达一组G蛋白偶联受体。其中一个受体，GPR116，是一种孤儿粘附性GPCR，以前没有发现在骨形成中的作用。初步研究表明，GPR116可以调节骨小梁的形成。这项建议的总体目标是用系统的方法从三个具体目标确定GPR116在骨骼中的作用：1)确定GPR116激活的信号通路；2)使用组织特异性基因敲除小鼠模型确定GPR116在成骨细胞中的生理学作用；以及3)使用人类诱导的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在调节骨小梁形成中的作用，并有助于我们理解粘附性GPCRs的功能。这些结果将为未来的研究建立一个强有力的框架，包括GPR116如何调控骨组织形成、肿瘤转移或异位骨形成。这项拟议的研究是一个协调的职业发展计划的一部分，目的是为候选人成为一名杰出的、独立的内科科学家做准备。在本奖项结束时，候选人将使用本研究的结果和试剂来申请独立研究人员奖，如NIH R01奖励。