Physiology of Bone Metabolism in an Aging Population

 描述(由申请人提供)：尽管骨质疏松症作为一个主要的和日益严重的公共健康问题的重要性现在得到了很好的认识，但我们对这种疾病的临床和基本理解仍然存在重大差距。因此，该计划项目赠款(PPG)的总体目标是更好地定义与年龄相关的骨丢失和骨折的发病机制和对人群的影响。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，目前的应用包括项目1中临床研究单位(CRU)的临床研究研究，项目2中的基于人群的流行病学研究，以及项目3中的基础小鼠/细胞研究。这三个项目由行政和生物统计学核心支持。尽管每个项目使用的方法不同，但本PPG的中心主题是更好地了解交感神经系统(SNS)在调节骨代谢和与年龄相关的骨丢失中的作用。因此，在雌激素(E)缺乏的绝经后妇女中，交感神经流出增加在促进骨形成障碍和骨吸收随年龄增加方面的影响由项目1的目标1解决，而与交感神经流出增加相关的一种重要的与年龄相关的临床疾病-心力衰竭(HF)的人口影响将在项目2的目标1中进行研究。 项目3将使用小鼠模型来研究SNS和E信号在骨骼中的潜在相互作用。每个项目的后续目标仍然与第一个目标密切相关，但涉及更多与年龄相关的骨丢失和骨折相关的项目特定问题。因此，项目1还将确定导致骨形成中与年龄相关的损害的其他基本机制。对于后一项研究，我们将利用我们实验室开发的新技术，从人的针骨活检中分离高度浓缩的成骨细胞和骨细胞群，并在不需要体外培养的情况下进行分析。项目2将加强骨折风险评估，并从人群角度确定临床相关的病理生理机制。因此，除了评估心衰对骨折风险的影响外，这些研究还将解决尚未解决的主要问题，即新出现的共病条件如何相互作用来确定骨折风险与年龄的关系。项目3将使用小鼠模型来研究SNS和E信号在骨骼中的潜在相互作用。这些研究还将通过有条件地删除雌激素受体[ERs]和成年小鼠填补关于E调节骨转换的重要知识空白，从而区分这些受体在骨骼发育和成年骨骼调节中的作用。核心将提供行政领导、关键基础设施以及所需的生物统计和生物信息学资源 这三个项目。

 DESCRIPTION (provided by applicant): While the importance of osteoporosis as a major, and growing, public health problem is now well recognized, there remain significant gaps in our clinical and basic understanding of this disorder. Thus, the overall goal of this Program Project Grant (PPG) is to better define the pathogenesis and population impact of age-related bone loss and fractures. As in the past, the major strength of our group is to bring together diverse disciplines into synergistic interactions, and the present application includes clinical-investigatve studies in the Clinical Research Unit (CRU) in Project 1, population-based epidemiology studies in Project 2, and basic mouse/cellular studies in Project 3. The three Projects are supported by an Administrative and Biostatistics Core. Although the approaches being used in each of the Projects differ, the central theme of this PPG, which is addressed by Aim 1 of each Project, is to better understand the role of the sympathetic nervous system (SNS) in regulating bone metabolism and age-related bone loss. Thus, the effects of increased sympathetic outflow in contributing to impaired bone formation and increased bone resorption with aging in estrogen (E)- deficient postmenopausal women are addressed by Aim 1 of Project 1, whereas the population impact of an important age-related clinical condition associated with increased sympathetic outflow, heart failure (HF), will be studied in Aim 1 of Project 2. Similarly, Aim 1 of Project 3 will use mouse models to examine potential interactions between SNS and E signaling in bone. Subsequent Aims of each Project remain closely related to the first Aim, but address more Project-specific issues relevant to age-related bone loss and fractures. Thus, Project 1 will also identify other, fundamental mechanisms responsible for the age-related impairment in bone formation. For the latter studies, we will utilize novel techniques developed in our laboratory to isolate highly enriched populations of osteoblasts and osteocytes from human needle bone biopsies and analyzed without the need for in vitro culture. Project 2 will enhance fracture risk assessment and identify clinically relevant pathophysiologic mechanisms from a population-based perspective. Thus, in addition to evaluating the impact of HF on fracture risk, these studies will address the major unresolved issue of how emerging comorbid conditions interact to determine fracture risk with aging. Project 3 will employ mouse models to examine potential interactions between SNS and E signaling in bone. These studies will also fill important gaps in knowledge regarding E regulation of bone turnover by using conditional deletion of estrogen receptors [ERs] and in adult mice, thereby differentiating the role of these receptors in skeleta development versus in regulation of the adult skeleton. The Core will provide administrative leadership, critical infrastructure, and the biostatistical and bioinformatics resources needed for the three Projects.