Physiology of Bone Metabolism in an Aging Population

描述（由申请人提供）：这是P01 AG 004875“老年人群骨代谢生理学”的竞争性更新申请。“骨质疏松症是一个巨大的公共卫生问题，我们的总体目标是更好地了解随着年龄增长骨质流失的机制和后果。与过去一样，我们小组的主要优势是将不同学科整合到一起，形成协同作用，目前的应用包括基于人群的流行病学研究，临床研究单位（以前的一般临床研究中心）的深入研究，使用新型小鼠模型的动物研究，以及基础细胞和分子研究。使用这种综合方法，我们建议集中在三个主要领域：（1）确定雌激素（E）调节骨代谢的机制;（2）随着骨吸收的增加，如在E缺乏的情况下，确定破骨细胞调节成骨细胞的机制;（3）评估骨折的风险因素和后果，增加E缺乏和老化。每个项目都与一个或多个主题相一致：项目1（“骨质疏松症的病理生理学”）使用人类作为实验模型来解决关于E对骨的作用的关键的、未解决的问题，包括明确地确定在E缺乏的情况下促卵泡激素是否调节骨吸收，以及确定与年龄相关的骨形成减少的机制;计划2（“老年人骨折的危险因素”）提供了关于骨折危险因素的人口观点（“继发性”骨质疏松症），加剧骨质流失与E缺乏和老化;项目3（“破骨细胞对骨形成的调节”）追求破骨细胞产生的调节骨形成的因子的基本生物学和功能相关性;和项目4（“骨中的雌激素受体信号通路”）使用体外和新型小鼠模型来剖析骨中的E信号通路。一个单一的核心（“行政和生物统计核心”）提供必要的基础设施，以支持这些项目。总的来说，这些研究努力提供一个全面的评估的发病机制和临床影响的一个最重要的疾病，我们面临的老龄化人口。

DESCRIPTION (provided by applicant): This is a competitive renewal application for P01 AG004875, "Physiology of Bone Metabolism in an Aging Population." Osteoporosis is an enormous public health problem, and our overall goal is to better understand the mechanisms and consequences of bone loss with aging. As in the past, the major strength of our group is to bring together diverse disciplines into synergistic interactions, and the present application includes population-based epidemiology studies, intensive studies in the Clinical Research Unit (formerly the General Clinical Research Center), animal studies using novel mouse models, and basic cellular and molecular studies. Using this integrated approach, we propose to focus on three major areas: (1) Defining the mechanisms by which estrogen (E) regulates bone metabolism; (2) With increases in bone resorption, as in the setting of E deficiency, identifying the mechanisms by which osteoclasts regulate osteoblasts; and (3) Assessing the risk factors for and consequences of fractures that increase with E deficiency and with aging. Each of the Projects are aligned with one or more of these major themes: Project 1 ("Pathophysiology of Osteoporosis") uses the human as the experimental model to address key, unresolved issues regarding E action on bone, including definitively establishing whether follicle-stimulating hormone modulates bone resorption in the setting of E deficiency and defining mechanisms for the age-related decrease in bone formation; Project 2 ("Risk Factors for Fractures Among the Elderly") provides a population perspective on risk factors for fractures ("secondary" osteoporosis) that exacerbate bone loss with E deficiency and with aging; Project 3 ("Osteoclast Regulation of Bone Formation") pursues the basic biology and functional relevance of factors made by osteoclasts that regulate bone formation; and Project 4 ("Estrogen Receptor Signaling Pathways in Bone") uses in vitro and novel mouse models to dissect E signaling pathways in bone. A single Core ("Administrative and Biostatistics Core") provides the necessary infrastructure to support these Projects. Collectively, these studies strive to provide a comprehensive assesment of the pathogenesis and clinical impact of one of the most important disorders facing our aging population.