Glucocorticoid Receptor Signaling in the Osteoblast and its Role in Osteoporosis

描述(由申请人提供)： 项目摘要：该应用程序建议作为医生-科学家的指导职业发展，为候选人提供必要的独立调查计划的基础。该候选人是一名学院型儿科内分泌学家，其职业目标是阐明糖皮质激素的作用机制，重点是了解糖皮质激素诱发的骨质疏松症(GIOP)。建议在华盛顿大学的Louis J.Muglia博士的实验室中进行的有指导的科学培训提供了一个理想的环境，使候选人能够发展成为一名独立研究人员的科学技能，同时与糖皮质激素(GC)生理学和信号传导方面的专家一起工作。在此期间，候选人还将接受骨代谢专家Steven Teitelbaum博士的骨生物学研究培训。在他的整个职业生涯中，候选人将保持专注和有限的儿科内分泌实践，这将指导他的研究努力，尽管大部分时间将投入临床相关研究。在拟议的项目中将检验的中心假设如下：(1)GC对成骨细胞的直接作用在GIOP中起主要作用，这一作用将被量化。(2)这些对成骨细胞的直接GC作用导致与GIOP相关的骨形成减少。(3)GC诱导的成骨细胞凋亡是通过成骨细胞糖皮质激素受体(GR)介导的，从而导致骨形成减少。(4)GCs通过GR调节甲状旁腺激素信号转导途径，引起成骨细胞的凋亡。候选人建议使用最近开发的一种独特的条件性基因敲除小鼠模型来检验这些假设，该模型可以使成骨细胞及其前体中的糖皮质激素受体失活。对这些成骨细胞GR缺陷小鼠和GR完整小鼠的比较分析将为上述问题提供答案。由此获得的信息将进一步了解GIOP，意在有朝一日开发出预防或避免骨丢失的药物。 与公共健康相关：糖皮质激素诱发的骨质疏松症(GIOP)目前是继绝经后和老年性骨质疏松症之后的第三大骨质疏松症原因，估计有30%-50%的人在长期GC治疗期间发生骨折。虽然糖皮质激素导致骨丢失和增加骨折的风险是显而易见的，但GIOP的机制尚不清楚，因此很难开发预防或改进的治疗方法。拟议研究项目的结果可能导致新的治疗牙周炎的选择，保留糖皮质激素有益的免疫调节作用，同时防止与使用它们相关的骨丢失。

DESCRIPTION (provided by applicant): Project Summary: This application proposes mentored career development as a physician-scientist to provide the candidate the foundation necessary for an independent investigative program. The candidate is an academic pediatric endocrinologist whose career goal is to elucidate the mechanisms of glucocorticoid action, with an emphasis on understanding glucocorticoid-induced osteoporosis (GIOP). The proposed period of mentored scientific training in the laboratory of Dr. Louis J. Muglia at Washington University provides an ideal environment to do so, allowing the candidate to develop the scientific skills to become an independent investigator while working alongside an expert in glucocorticoid (GC) physiology and signaling. During this period the candidate will also receive training in the study of bone biology from Dr. Steven Teitelbaum, an expert in bone metabolism. Throughout his career the candidate will maintain a focused and limited pediatric endocrine practice that will guide his research endeavors, though the majority of time will be devoted to clinically relevant research. The central hypotheses that will be tested during the proposed project are as follows: (1) Direct effects of GC on the osteoblast play a major role in GIOP, which will be quantified. (2) These direct GC effects on the osteoblast cause the decrease in bone formation associated with GIOP. (3) GC-induced osteoblast apoptosis, which contributes to the decrease in bone formation, is mediated by the osteoblast glucocorticoid receptor (GR). (4) GCs, through the GR, cause apoptosis in the osteoblast through modulation of specific aspects of PTH signaling. The candidate proposes to test these hypotheses using a recently developed, unique conditional knockout mouse model that inactivates the glucocorticoid receptor in osteoblasts and their precursors. The comparative analysis of these osteoblast GR-deficient mice with GR intact mice will provide answers to the above questions. Information thus gained will further understanding of GIOP, with the intention of one day developing agents that prevent or avoid the bone loss. Relevance to Public Health: Glucocorticoid-induced osteoporosis (GIOP) is now the third leading cause of osteoporosis following post menopausal and senile varieties, and an estimated 30-50% of people experience a fracture during chronic GC treatment. Though it is clear that glucocorticoids cause bone loss and increase the risk of fracture, the mechanism of GIOP is not clear, and therefore it is difficult to develop preventative or improved therapies. Results from the proposed research project may lead to new treatment options for GIOP that preserve the beneficial immunomodulatory effects of glucocorticoids while preventing the bone loss associated with their use.