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.

项目摘要 社交孤立是一种潜在的心理压力，也是一个日益严重的公共卫生问题。老年人， 特别是那些在COVID-19大流行期间被隔离的人，尤其脆弱。四分之一 据估计，65岁以上的人受到社会孤立和孤独的影响， 与死亡风险增加高达70%相关。以前的研究表明， 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。尽管社会 隔离和高危人群之间的重叠，很少有关于社会影响的研究。 隔离对骨丢失和骨骼代谢的影响。在啮齿类动物中所做的有限工作表明， 社会隔离对骨骼健康产生负面影响，导致骨矿物质密度降低。没有这些 然而，研究已经探索了隔离诱导的骨丢失的机制，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， 社会隔离降低了股骨骨体积分数、骨矿物质密度和皮质厚度。 相反，女性骨量没有任何减少。我的数据还显示， 糖皮质激素受体和β2肾上腺素能受体的表达作为社会隔离的结果，这两者都有 对骨骼的影响。因此，本项目的目标是测试总体假设，即社会 隔离通过改变糖皮质激素（目的1）和交感神经系统（目的2）导致骨丢失 活动我将使用一个4到8周的老鼠模型来测试这些假设，这个模型是在16周大的老鼠中进行的。 小鼠，结合药理学和遗传学方法。我还会用蛋白质组学和微RNA 排序方法，以确定新的系统性变化，以应对可能影响 骨头这项拟议的项目将是第一项研究，以确定社会孤立引起的中介机制， 通过一系列成像，遗传， 组织学和组学方法。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治疗的个人在最大的风险，社会 隔离