Investigating the Impact of Social Isolation on Bone Metabolism

研究社会隔离对骨代谢的影响

• 批准号: 10722595
• 负责人: Rebecca Mountain
• 金额: $ 12.74万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10722595
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Adrenergic Agents; Affect; Anxiety; Architecture; Biological Markers; Bone Density; Bone Marrow; Bone Resorption; Brain; COVID-19 pandemic; Catecholamines; Clinical; Clinical Research; Clinical Treatment; Corticosterone; Data; Disease; Elderly; Exposure to; Female; Femur; Fracture; Future; Gene Expression; Genes; Genetic; Glucocorticoid Receptor; Glucocorticoids; Goals; Health; Histologic; Homeostasis; Human; Image; Individual; Knockout Mice; Loneliness; Long-Term Effects; Measures; Mediating; Mental Depression; Mental Health; Mental disorders; Metabolic; Metabolism; Metyrapone; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; NADH dehydrogenase (ubiquinone); Osteogenesis; Osteoporosis; Outcome; Phase; Phenotype; Physiological; Populations at Risk; Prevalence; Prevention strategy; Propranolol; Proteomics; Psyche structure; Psychosocial Stress; Public Health; Research; Risk; Rodent; Role; Serum; Sex Differences; Signal Transduction; Social isolation; Stress; Sympathetic Nervous System; Testing; Thick; Time; Work; antagonist; beta-2 Adrenergic Receptors; biological sex; bone; bone health; bone loss; bone mass; bone metabolism; circulating microRNA; coping; epidemiology study; experience; fracture risk; genetic approach; human old age (65+); inhibitor; lonely individuals; male; miRNA expression profiling; mortality; mortality risk; mouse model; neural; novel; pharmacologic; prevent; receptor; receptor expression; response; sex; skeletal; stress disorder; substantia spongiosa; therapeutic target; treatment strategy

PROJECT SUMMARY Social isolation is a potent form of psychosocial stress, and a growing public health concern. Older adults, particularly those individuals isolated during the COVID-19 pandemic, are particularly vulnerable. One in four individuals over the age of 65 are estimated to be affected by social isolation and loneliness, which are associated with an increase in mortality risk by up to 70%. Previous studies have shown other forms of psychosocial stress and mental illness are associated with increased risk for osteoporosis and related fractures, which are likewise associated with increased mortality in older adults. Despite the increase in social isolation and the overlap between at-risk populations, there has been little research on the effects of social isolation on bone loss and skeletal metabolism. The limited work that has been done in rodents suggest that social isolation negatively impacts bone health, leading to decreased bone mineral density. None of these studies, however, have explored the mechanisms of isolation-induced bone loss, or examined differences in the effect of isolation on bone between the sexes. My own preliminary studies show that males exposed to social isolation had reduced femoral bone volume fraction, bone mineral density, and cortical thickness. Females, conversely, did not have any reduction in bone mass. My data also showed changes to glucocorticoid receptor and β2 adrenergic receptor expression as a result of social isolation, which both have known effects on bone. The goal of this project is therefore to test the overarching hypothesis that social isolation leads to bone loss through altered glucocorticoid (Aim 1) and sympathetic nervous system (Aim 2) activity. I will test these hypotheses using a 4 to 8-week-long mouse model of social isolation in 16-week old mice, in combination of pharmacological and genetic approaches. I will also use proteomic and microRNA sequencing approaches to identify novel systemic changes in response to social isolation that may impact bone. The proposed project will be the first study to identify mediating mechanisms of social isolation-induced bone loss and precisely test the effects of isolation on bone metabolism through a range of imaging, genetic, histologic, and omic approaches. The results of this project will inform future clinical and epidemiological studies, and help identify prevention strategies and treatments for individuals at the greatest risk for social isolation.

项目总结 社会孤立是心理社会压力的一种有效形式，也是一个日益严重的公共卫生问题。上了年纪的人， 特别是那些在新冠肺炎大流行期间被隔离的人，特别容易受到伤害。每四个人中就有一个 据估计，65岁以上的人会受到社会孤立和孤独的影响，这是 与高达70%的死亡风险相关。以前的研究已经表明，其他形式的 心理社会压力和精神疾病与骨质疏松症的风险增加有关 骨折，这同样与老年人死亡率的增加有关。尽管社交媒体增加了 与世隔绝和高危人群之间的重叠，几乎没有关于社会影响的研究 隔离骨丢失和骨骼代谢。在啮齿动物身上所做的有限的研究表明 社交隔离会对骨骼健康产生负面影响，导致骨密度下降。这些都不是 然而，研究已经探索了隔离导致骨丢失的机制，或者检查了 隔离对两性骨骼的影响。我自己的初步研究表明，暴露在 社会隔离降低了股骨体积分数、骨密度和皮质层厚度。 相反，女性的骨量没有任何减少。我的数据还显示更改为 糖皮质激素受体和β-2肾上腺素能受体的表达是社会隔离的结果，两者都有 已知的对骨骼的影响。因此，这个项目的目标是检验一个最重要的假设 隔离通过改变糖皮质激素(目标1)和交感神经系统(目标2)导致骨丢失 活动。我将使用一个长达4到8周的16周龄小鼠的社交隔离模型来检验这些假设 小鼠，结合药理学和遗传学方法。我还将使用蛋白质组学和microRNA 确定响应于可能影响社会隔离的新的系统变化的排序方法 骨头。这项拟议的项目将是第一个确定社会孤立导致的中介机制的研究 骨丢失，并通过一系列成像、遗传学、 组织学和基因组学方法。该项目的结果将为未来的临床和流行病学提供信息。 研究并帮助确定预防策略和针对社会风险最大的个人的治疗方法 与世隔绝。