PHYSIOLOGY OF BONE METABOLISM IN AN AGING POPULATION

这是P-01 AG 04875“老龄人口骨代谢生理学”16-20年的竞争性续期申请。骨质疏松症是与衰老相关的最重要疾病之一，也是影响妇女健康的最重要问题之一。骨质疏松导致的骨折在残疾和费用方面造成了惊人的损失。白人女性一生中发生一次或多次骨质疏松相关骨折的风险为40%-50%，黑人女性或白人男性的风险为三分之一。在美国，骨质疏松症每年至少造成150万例骨折，并使医疗保健系统花费140亿美元。我们的总体目标是更好地了解与年龄相关的骨质流失和骨质疏松症的原因，以便制定更有效的治疗和预防策略。该项目资助申请包括采用不同调查学科和行政/统计核心的项目，这些项目相互作用，协同作用，两者可以比单独取得更快的进展。“骨质疏松的病理生理学”是临床调查部分。新发现的抗骨吸收和促骨吸收细胞因子——骨蛋白素及其相关配体——是否是雌激素(E)作用于骨骼的旁分泌介质，其分泌异常是否会导致绝经后骨质疏松症，以及E缺乏是否在老年男性骨质流失中起主要的因果作用。“髋部骨折的危险因素”是流行病学部分，以一系列独特的、基于人群的回顾性（非当前的、历史的）队列研究为特色，旨在评估某些疾病、药物和生活方式差异对骨折发生率的影响。“性类固醇、生长因子和骨细胞功能”是基础科学部分，重点关注性类固醇对骨细胞功能的调节。它将解决骨细胞生物学中当前最重要的两个问题-雌激素受体α和β物种浓度变化对骨细胞功能的影响以及骨细胞中E的主要旁分泌介质的鉴定。

This is a competitive renewal application for funding of years 16-20 of P-01 AG 04875 "Physiology of Bone Metabolism in an Aging Population." Osteoporosis is one of the most important diseases associated with aging and one of the most important issues affecting women's health. Fractures due to osteoporosis exact a staggering toll in disability and expense. The lifetime risk of having one or more fractures associated with osteoporosis is 40%-50% for a White women and is one third of this for a Black woman or a White man. Each year osteoporosis causes at least 1.5 million fractures and costs the health care system $14 billion in the United States. Our overall goal is to understand the causes of age-related bone loss and osteoporosis better so as to develop more effective strategies for their treatment and prevention. This program grant application comprises projects employing different investigative disciplines and an administrative/statistical core that interact synergistically two permit more rapid progress than could be achieved by each alone. "Pathophysiology of Osteoporosis," is the clinical investigative component. Among the novel hypotheses that will be tested are whether the newly discovered anti-resorptive and pro-resorptive cytokines-osteoprotegrin and its cognate ligand-are the paracrine mediators of estrogen (E) action on bone and abnormalities in their secretion contribute to postmenopausal osteoporosis and whether E deficiency plays a major causal role in bone loss in aging men. "Risk Factors for Hip Fractures," the epidemiology component, features a series of unique, population-based retrospective (non-current, historical) cohort studies designed to assess the effects of certain diseases, drugs, and lifestyle differences on the incidence of fractures. "Sex Steroids, Growth Factors, and Bone Cell Function," the basic science component, focuses on sex steroid regulation of bone cell function. It will address two of the most important current issues in bone cell biology- the effect of changes in the concentration of the alpha and beta species of estrogen receptors on bone cell function and the identify of the major paracrine mediator of E on bone cells.