Pyschosocial Stress and the Response to Stroke

项目摘要 社会隔离(SI)预测多种健康状况的发病率和死亡率， 包括癌症、心血管疾病和中风。社会支持水平高的患者 或大型社交网络在中风后表现出更快和更广泛的功能恢复 社交孤立的个体，这些因素对老年人的影响似乎更大 女人。社会互动通过促进适应性来克服SI的有害影响 对生物应激源的行为和有利的神经内分泌反应。尽管有巨大的 SI对卒中后恢复的影响，没有研究试图减轻其有害影响 使用基于目标的方法对神经行为结果进行隔离。 MicroRNAs(MiRNAs)是一种短小的非编码RNA，正在成为一种强大的干预手段 治疗包括中风在内的许多疾病的工具。它们调控着一系列广泛的生物途径 通过微调蛋白质表达水平和改变基因表达水平。他们有 能够同时靶向疾病病理中涉及的多个途径的效应器。 最近的研究发现，microRNAs在社会互动的许多方面起着中介作用， 这使我们假设，miRNA调节参与了SI后的卒中后病理。 初步研究发现，包括miR-181c-5p和miR-181c-5p在内的几种miRNAs表达 MiR-124-5p，参与调节炎症、长时程增强和 神经营养因子信号，是由老年小鼠中风后隔离所调节的。在这份提案中，我们 将确定哪些miRNAs在分离的老年雄性和雌性小鼠中有差异表达 卒中后，确定是阻断(基因缺失或对映体)还是增强(模仿) 这些靶标miRNA调节它们的作用。这项提案的总体目标是确定是否 操纵靶miRNAs可促进老年动物卒中后功能恢复 遭受SI，这是恢复不佳的主要风险因素。

Project Summary Social isolation (SI) predicts morbidity and mortality from a multitude of health conditions, including cancer, cardiovascular disease, and stroke. Patients with high levels of social support or large social networks exhibit more rapid and extensive functional recovery after stroke than socially isolated individuals, and the impact of these factors appears to be greater in elderly women. Social interaction overcomes the detrimental effects of SI by promoting adaptive behaviors and favorable neuroendocrine responses to biological stressors. Despite the huge impact of SI on post-stroke recovery, no study has attempted to mitigate the detrimental effects of isolation on neurobehavioral outcomes using target-based approaches. MicroRNAs (miRNAs) are short non-coding RNAs that are emerging as a powerful intervention tool for many diseases including stroke. They regulate a broad spectrum of biological pathways through fine-tuning of protein expression levels and altering gene expression levels. They have the ability to concurrently target multiple effectors of pathways involved in disease pathology. Very recent studies have found that microRNAs mediate many aspects of social interaction, leading us to hypothesize that miRNA regulation is involved in post-stroke pathology after SI. Preliminary studies have found that expression of several miRNAs including miR-181c-5p and miR-124-5p, which are involved in regulation of inflammation, long term potentiation and neurotrophin signaling, are modulated by post-stroke isolation in aged mice. In this proposal we will determine which miRNAs are differentially expressed in aged male and female mice isolated after stroke and determine if blocking (with genetic deletion or antagomirs) or enhancing (mimics) these target miRNA modulates their effects. The overall goal of this proposal is to determine if manipulation of target miRNAs can improve functional recovery after stroke in aged animals subjected to SI, a major risk factor for poor recovery.