Pyschosocial Stress and the Response to Stroke

项目摘要 社会隔离（SI）可以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， 社会孤立的个人，这些因素的影响似乎是更大的老年人 妇女社会互动通过促进适应性， 行为和良好的神经内分泌反应的生物应激。尽管存在巨大 SI对中风后恢复的影响，没有研究试图减轻不利影响 神经行为结果的隔离使用基于目标的方法。 microRNAs（miRNAs）是一种短的非编码RNA， 治疗包括中风在内的多种疾病的工具。它们调节着广泛的生物途径 通过微调蛋白质表达水平和改变基因表达水平。他们有 同时靶向疾病病理学中涉及的途径的多个效应物的能力。 最近的研究发现，microRNA介导了社会互动的许多方面， 这使我们假设miRNA调节参与SI后的中风后病理学。 初步研究发现，包括miR-181 c-5 p和miR-181 c-5 p在内的几种miRNAs的表达与细胞凋亡有关。 miR-124- 5 p参与炎症、长时程增强和 神经营养因子信号传导，通过老年小鼠中风后隔离来调节。在本提案中，我们 将确定哪些miRNAs在分离的老年雄性和雌性小鼠中差异表达 中风后，并确定是否阻断（与基因缺失或基因突变）或增强（模拟） 这些靶向miRNA调节它们的作用。本提案的总体目标是确定， 靶向miRNA的操作可以改善老年动物中风后的功能恢复 受到SI的影响，这是恢复不良的主要风险因素。

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.