Molecular & cellular Mechanisms of Osteoporosis

分子

• 批准号: 7638949
• 负责人: STAVROS C. MANOLAGAS
• 金额: $ 2万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638949
• 关键词: Address; Adrenal Glands; Adverse effects; Age; Age-Related Bone Loss; Aging; Antioxidants; Apoptosis; Birth; Bone Density; Bone Marrow; C57BL/6 Mouse; Cellular biology; Cessation of life; Classification; Daily; Deterioration; Dissection; Elderly; Enzymes; Estrogens; Fatigue; Generations; Glucocorticoids; Goals; Injection of therapeutic agent; Knockout Mice; Link; Mechanics; Mediating; Modality; Molecular; Numbers; Organ; Osteoblasts; Osteocytes; Osteoporosis; Ovary; Phosphotransferases; Physical activity; Population; Prevalence; Process; Production; Property; Reactive Oxygen Species; Relative (related person); Risk Factors; Skeletal system; Skeleton; System; Testing; Therapeutic; Tissues; Transgenic Organisms; Work; age related; bone; bone cell; bone quality; bone strength; bone turnover; fluid flow; lipid biosynthesis; oxidized lipid; programs; repaired; transcription factor

DESCRIPTION (provided by applicant): The objective of this renewal application is three-fold. First, we plan to capitalize on our accomplishments in the last 10 years and provide a comprehensive dissection of the contribution of age-related changes in other organs or tissues (e.g., ovaries, bone marrow, adrenals), and the cellular and molecular mechanisms behind them, to the age-related loss of bone mass and strength versus the contribution of skeletal aging per se. Second, we will establish the impact of aging on various qualitative aspects of bone strength, including microarchitecture, prevalence of fatigue damage, bone turnover, and osteocyte number. Third, we will investigate the relative efficacy and mechanistic appropriateness of different therapeutic modalities on the aging skeleton in the context of the specific pathogenetic factors that contribute to age-associated osteoporosis. To achieve the goal of the Program, four Projects (supported by three Cores) will address, in a thematic and systematic manner, closely interrelated hypotheses, which will be tested using a variety of molecular and cell biology approaches, as well as normally aging C57BL/6 mice, and several other transgenic and knockout mice. In Project 1, the contribution of estrogen loss to the age-related loss of bone mass and strength will be investigated by exploring the molecular mechanisms of the skeletal effects of estrogens in old age, and in particular, the compelling link among the antioxidant properties of estrogens, cytoplasmic kinase-mediated estrogen actions, reactive oxygen species, and the birth and death of bone cells with old age. Project 2 will examine the contribution of oxidized lipids (and the enzymes responsible for their generation, e.g., Alox15, or the transcription factors that mediate their actions, e.g., PPARy), to the decreased osteoblastogenesis and increased adipogenesis that occurs with old age; and the exciting possibility that daily injections of PTH are rational therapy for age-related osteoporosis because they ameliorate the adverse effects of reactive oxygen species and oxidized lipids on osteoblast apoptosis. Project 3 will seek a mechanistic explanation for why age is a far more critical risk factor for fractures than bone mineral density. Specifically, we will study the impact of the age-related increase in glucocorticoid production on the integrity of the osteocyte/lacunarcanalicular system, fluid flow, material properties and the accumulation of damaged bone; and the contribution of these factors on the mismatch between bone strength and BMD. Finally, Project 4 will explore the possibility that reduced mechanical forces during aging (from reduced physical activity) increase osteocyte apoptosis and this leads to deterioration of bone quality and an aberrant repair process, both of which contribute to decreased bone strength. This work should help us better understand why elderly people suffer from osteoporosis a lot more than young people; and perhaps identify the optimal anti-osteoporosis therapy for this particular segment of the population.

描述（由申请人提供）：此续签申请的目的是三倍。首先，我们计划在过去10年中利用我们的成就，并全面解剖其他器官或组织中与年龄相关的变化的贡献（例如，卵巢，骨髓，肾上腺），以及在其背后的细胞和分子机制，对与年龄相关的骨骼质量和强度损失与骨骼的损失相关的损失。其次，我们将建立衰老对骨强度各种定性方面的影响，包括微体系结构，疲劳损伤的流行，骨骼更新和骨细胞数。第三，我们将在衰老的骨骼中研究不同治疗方式的相对疗效和机械适当性，这是在有助于与年龄相关的骨质疏松症的特定致病因素的背景下。为了实现该计划的目标，四个项目（由三个核心支持）将以主题和系统的方式紧密相互关联的假设来解决，该假设将使用各种分子和细胞生物学方法以及通常衰老的C57BL/6小鼠以及其他几种转基因和敲除小鼠进行测试。在项目1中，将通过探索雌激素损失对年龄相关的骨骼质量和强度的损失的贡献，可以通过探索雌激素在老年时的骨骼作用的分子机制，尤其是雌激素的抗氧化特性之间的引人注目的联系，细胞酶介导的雌激素介导的雌激素造成的骨骼和生育物种，且生育物种。项目2将检查氧化脂质的贡献（以及负责产生的酶，例如Alox15或介导其作用的转录因子，例如PPARY），对骨细胞生成的降低和增加的脂肪生成，而随着年龄的增长；每天对PTH注射的令人兴奋的可能性是对年龄相关的骨质疏松症的合理疗法，因为它们可以改善活性氧和氧化脂质对成骨细胞细胞凋亡的不利影响。项目3将寻求一种机械解释，说明为什么年龄比骨矿物质密度要比骨折更为关键的危险因素。具体而言，我们将研究糖皮质激素生产与年龄相关的增加对骨细胞/lacunarcanalcanalcarcular系统的完整性，流体流动，材料特性和受损骨的积累的影响；这些因素对骨骼强度和BMD之间的不匹配的贡献。最后，项目4将探索衰老过程中降低机械力（由于体育锻炼减少）增加骨细胞凋亡的可能性，这导致骨质质量恶化和异常修复过程，这两者都会导致骨骼强度降低。这项工作应该有助于我们更好地理解为什么老年人比年轻人更多地患有骨质疏松症。也许可以确定针对这一特定人群的最佳抗骨病疗法。