Physiology of Bone Metabolism in an Aging Population

描述(由申请人提供)：这是P01 AG004875的竞争性续签申请，“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随着年龄增长而导致的骨丢失的机制和后果。与过去一样，我们团队的主要优势是将不同学科整合为协同互动，目前的应用包括基于人群的流行病学研究、临床研究单位(前临床研究中心)的密集研究、使用新型小鼠模型的动物研究，以及基础细胞和分子研究。使用这一综合方法，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；以及(3)评估因E缺乏和随着年龄增加而增加的骨折的危险因素和后果。每个项目都与这些主要主题中的一个或多个相一致：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”)提供了关于骨折(“继发性”骨质疏松症)危险因素的人群视角，这些危险因素加剧了E缺乏和衰老时的骨丢失；项目3(《破骨细胞对骨形成的调控》)致力于研究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；项目4(《骨中的雌激素受体信号通路》)利用体外和新颖的小鼠模型来剖析骨中的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。总而言之，这些研究致力于全面评估老年人口面临的最重要的疾病之一的发病机制和临床影响。

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.