Physiology of Bone Metabolism in an Aging Population

描述（由申请人提供）：这是P01 AG004875的竞争性更新申请，“老龄化人口中的骨代谢生理学”。骨质疏松症是一个巨大的公共健康问题，我们的总体目标是更好地了解骨质流失与衰老的机制和后果。与过去一样，我们小组的主要优势是将不同学科整合到协同互动中，目前的应用包括基于人群的流行病学研究，临床研究部门（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，以及基本的细胞和分子研究。利用这种综合方法，我们建议关注三个主要领域：(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)评估随着E缺乏和年龄增长而增加的骨折的危险因素和后果。每个项目都与以下一个或多个主要主题相一致：项目1（“骨质疏松的病理生理学”）使用人类作为实验模型来解决有关E对骨骼作用的关键未解决的问题，包括明确确定促卵泡激素是否在E缺乏的情况下调节骨吸收，并确定与年龄相关的骨形成减少的机制；项目2（“老年人骨折的危险因素”）从人口角度研究骨折（“继发性”骨质疏松症）的危险因素，这些因素会随着E缺乏和年龄增长而加剧骨质流失；项目3（“破骨细胞调控骨形成”）研究破骨细胞调控骨形成因子的基本生物学和功能相关性；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解剖骨中的E信号通路。单一核心（“行政和生物统计核心”）为支持这些项目提供必要的基础设施。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最重要的疾病之一，面临我们的老龄化人口。

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.