A New Regulator of Trabecular Bone Formation

骨小梁形成的新调节器

• 批准号: 8434752
• 负责人: EDWARD C HSIAO
• 金额: $ 13.54万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434752
• 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 Profiling; 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）：影响骨骼和关节的项目摘要/摘要肌肉骨骼疾病是一个日益严重的健康问题。在美国，骨质疏松症影响超过1000万人。此外，骨折每年导致超过300万个急诊室就诊。由于我们治疗和预防这些疾病的能力仍然非常基本，因此阐明调节骨骼形成的机制对于理解骨骼疾病的病理变化和开发靶向治疗以增加骨形成至关重要。先前的结果确定了一组G蛋白偶联受体，该受体在激活GS-GPCR信号通路后在成骨细胞中高度表达。这些受体之一GPR116是一种孤儿粘附GPCR，在骨形成中没有先前鉴定的作用。初步研究表明，GPR116可以调节小梁骨形成。该提案的总体目的是在三个特定目的中使用系统的方法来定义GPR116在骨骼中的作用：1）确定GPR116激活的信号传导途径； 2）使用组织特异性的敲除小鼠模型确定GPR116在成骨细胞中的生理作用； 3）确定GPR116是否使用人类诱导的多能茎（IPS）细胞模型系统来调节软骨或骨骼的形成。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，并有助于我们理解粘附GPCR的功能。结果将为未来的研究建立一个强大的框架，包括GPR116如何调节骨骼组织形成，肿瘤转移或异位骨形成。拟议的研究是一项协调的职业发展计划的一部分，旨在使候选人成为杰出的独立医师科学家。在该奖项结束时，候选人将使用这项研究的结果和试剂申请独立调查员奖，例如NIH R01赠款。