Extracellular Vesicle Analyses to Develop Aging and Resilience Biomarkers

摘要 细胞外小泡(EV)是几乎所有类型的细胞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。取决于来源组织、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。虽然 组织水平的弹性在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 生产电动汽车，作为其非凡的再生能力的中介。小型电动汽车的快速发布是 由身体活动引起的，并被认为有助于有规律的运动对 肌肉新陈代谢、心血管系统以及免疫调节。这个项目的目标是 通过对电动汽车的分析，开发老化和弹性的生物标记物。由于他们的协调监管 通过微小RNA和蛋白质货物的细胞间运输实现组织动态平衡和生物过程 电动汽车对这个项目特别有吸引力，因为它们可能成为 衰老和韧性，即衰老过程和对应激源的反应的指标和中介。我们会 使用我们最新开发的18通道高分辨率流式细胞仪方法，并通过 纳米颗粒跟踪视频显微镜，以及我们在 实验室评估我们现有的大量人类样本集(来自EPESE的4213人， PALS、STRRIDE、BHS和Duke 1KP(1000名患者)队列)，以及相关的已确定数据和 纵向随访6个月~23年。我们有初步数据显示与年龄相关的下降 在流通中的电动汽车的特定子集中。我们还确认了电动汽车的一部分，包括其中一些 随着年龄的增长而下降，是由运动训练引起的，并预测对运动的有益新陈代谢反应。 这些数据，再加上我们这个项目的合作者，汇聚了老龄化方面的广泛专业知识， 在整个生命周期(18岁至102岁)中的韧性、锻炼和身体表现。这些资源 和能力为我们提供了一个独特的机会，使电动汽车沿着生物标记物管道显著前进 并确定健康、衰老和韧性的影响因素。出于这个原因，我们正在对资金做出回应 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 设置或存储生物样品，以解决影响健康的衰老变化的临床相关问题 寿命。

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.