Extracellular Vesicle Analyses to Develop Aging and Resilience Biomarkers

细胞外囊泡分析以开发衰老和弹性生物标志物

• 批准号: 10318917
• 负责人: Virginia Kraus
• 金额: $ 64.65万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10318917
• 关键词: Address; Age; Aging; Antigen-Presenting Cells; Autophagocytosis; Baltimore; Behavior; Biological Markers; Biological Models; Biological Process; Biology; Blood; Cardiovascular system; Cell Aging; Cell model; Cells; Chondrocytes; Clinical; Cohort Studies; Collaborations; Complex; Data; Data Set; Data Store; Defect; Elderly; Exercise; Fibroblasts; Fluorescence; Funding; Funding Opportunities; Goals; Health; Hematopoietic stem cells; Hip Fractures; Hip region structure; Homeostasis; Human; Immune; Immune system; In Vitro; Individual; Inflammation; Interleukin-6; Knowledge; Laboratories; Liquid substance; Literature; Longevity; Mammalian Cell; Measures; Mediating; Mediator of activation protein; Metabolic; Methodology; Methods; MicroRNAs; Microscopic; Mitochondria; Mitochondrial RNA; Mus; Myocardial Ischemia; Natural Killer Cells; Nucleic Acids; Operative Surgical Procedures; Organism; Outcome; Oxidative Stress; PECAM1 gene; Parents; Participant; Patients; Phenotype; Physical Performance; Physical activity; Physiological; Plasma; Play; Population; Process; Production; Proteins; Proteome; Randomized; Recovery; Regenerative capacity; Regulation; Reperfusion Injury; Resolution; Resources; Role; Sampling; Serum; Sorting - Cell Movement; Specimen; Supervision; Surface; Testing; Tissues; United States National Institutes of Health; Validation; Vesicle; Video Microscopy; WI 38 cell; age related; aged; base; cell type; cohort; cytokine; data de-identification; epidemiology study; exercise intensity; exercise training; extracellular vesicles; follow-up; immune function; immunoregulation; immunosenescence; insulin sensitivity; interest; milliliter; mode of exercise; muscle metabolism; nanoparticle; particle; peripheral blood; predictive marker; protein metabolite; resilience; responders and non-responders; response; secondary analysis; senescence; specific biomarkers; stem cells; stressor; trafficking; vesicular release

Abstract Extracellular vesicles (EVs) are membranous particles released from nearly all cell types into all bodily fluids evaluated to date — including serum and plasma. Depending on tissue of origin, health state and organism age, they carry a variety of complex cargo consisting of nucleic acids, proteins and metabolites. Although resilience at a tissue level has largely been attributed to stem cells, recent evidence increasingly points to their production of EVs as mediators of their remarkable regenerative capacity. The rapid release of small EVs is induced by physical activity and believed to contribute to the long-term beneficial effects of regular exercise on muscle metabolism, the cardiovascular system as well as immune modulation. The goal of this project is to develop biomarkers of aging and resilience through analyses of EVs. Due to their coordinate regulation of tissue homeostasis and biological processes through intercellular trafficking of microRNA and protein cargo, EVs are particularly attractive for this project because they can potentially serve as DIRECT biomarkers of aging and resilience, namely indicators AND mediators of the aging process and response to stressors. We will use our newly developed 18-channel-high-resolution flow cytometric methodology with validation by nanoparticle tracking video microscopy, and fluorescence-activated particle sorting that we have established in the laboratory to evaluate our large existing extensive human sample sets (n=4213 individuals from EPESE, PALS, STRRIDE, BHS and the Duke 1KP (1000 Patient) cohort) with associated deidentified data and longitudinal follow-up (6 months to 23 years). We have preliminary data demonstrating an age-related decline in specific subsets of circulating EVs. We also have identified that a subset of EVs, including some of those declining with age, are induced with exercise training and predict a beneficial metabolic response to exercise. These data, together with our collaborators for this project, bring together extensive expertise in aging, resilience, exercise, and physical performance across the lifespan (ages 18 to 102 years). These resources and capabilities provide a unique opportunity for us to significantly advance EVs along a biomarker pipeline and to identify effectors of heathy aging and resilience. For this reason, we are responding to the funding Opportunity Announcement PA-17-088 that invites applications that employ secondary analysis of existing data sets or stored biospecimens to address clinically related issues on aging changes influencing health across the lifespan.

抽象的 细胞外囊泡 (EV) 是几乎所有细胞类型释放到所有体液中的膜颗粒 迄今为止的评估——包括血清和血浆，取决于组织来源、健康状况和生物体。 随着年龄的增长，它们携带着由核酸、蛋白质和代谢物组成的各种复杂货物。 组织水平的恢复力很大程度上归因于干细胞，最近的证据越来越多地表明它们 电动汽车的生产是其卓越的再生能力的中介者 小型电动汽车的快速释放是。 由体力活动引起，并被认为有助于定期锻炼对身体产生长期有益影响 该项目的目标是肌肉代谢、心血管系统以及免疫调节。 通过对 EV 的协调调节，开发衰老和恢复力的生物标志物。 通过 microRNA 和蛋白质货物的细胞间运输实现组织稳态和生物过程， 电动汽车对该项目特别有吸引力，因为它们有可能作为直接生物标志物 衰老和复原力，即衰老过程和压力源反应的指标和中介。 使用我们新开发的 18 通道高分辨率流式细胞术方法并经过验证 我们在纳米颗粒跟踪视频显微镜和荧光激活颗粒分选方面建立了 实验室评估我们现有的大量人类样本集（n=4213 名来自 EPESE 的个体， PALS、STRRIDE、BHS 和 Duke 1KP（1000 名患者）队列）以及相关的去识别化数据和 纵向随访（6 个月至 23 岁）我们有初步数据表明年龄相关的下降。 在循环电动汽车的特定子集中，我们还确定了电动汽车的一个子集，包括其中的一些。 随着年龄的增长而下降，是通过运动训练诱发的，并预测对运动的有益代谢反应。 这些数据与我们该项目的合作者一起汇集了老龄化方面的广泛专业知识， 整个生命周期（18 至 102 岁）的复原力、锻炼和身体表现。 和能力为我们提供了一个独特的机会，可以沿着生物标记管道显着推进电动汽车 并确定健康老龄化和复原力的影响因此，我们正在响应这笔资金。 机会公告 PA-17-088，邀请对现有数据进行二次分析的应用程序 设置或存储生物样本，以解决影响整个健康的衰老变化的临床相关问题 寿命。