MicroRNA Endotypes of Systemic Inflammation in Sub-Arachnoid hemorrhaGE (MESSAGE)

项目总结 动脉瘤性蛛网膜下腔出血(SAH)对于年轻患者来说是不成比例的致命性和致命性的，原因 广泛的长期残疾，并给社会造成重大的健康经济负担。SAH是一家 非均质条件。SAH的一个独特特征是，除了脑损伤外，患者还可以发展为 伴有多个脑外器官功能障碍和全身炎性疾病的急性和严重系统性疾病 反应综合征。最近的几项SAH临床试验都未能显示出治疗效果，部分原因是 疾病异质性程度高。SAH治疗突破的一个主要障碍是缺乏 合适的生物标记物用于识别最有可能发生后续损伤、并发症和不良结局的患者 在这个异质的种群中。 内型是由不同的病理生理机制定义的生物学亚型，可以通过以下方式识别 相应的生物标志物。新内型的发现导致了癌症治疗的重大突破 以及自身免疫性疾病。MicroRNAs(MiRs)是一类具有理想特性的新型分子，如 SAH全身反应的潜在生物标志物，因为miRs在血液中非常稳定，在它们的 来源和目的地的细胞，可以通过调节基因表达来调节受体细胞的生物学过程， 已知具有调节炎症和免疫功能的作用。我们有很有希望的初步数据显示 蛛网膜下腔出血后早期血miR-26a升高与良好的长期预后相关，并可能降低 迟发性脑缺血(DCI)的风险，这是发病率的主要原因。 我们假设血液miR-26a是SAH长期预后的早期生物标志物，miR-26a可能 调节全身炎症宿主反应，减少迟发性脑缺血(DCI)。我们建议 同时在现有SAH患者队列和生物库中研究miR-26a作为潜在生物标记物的作用 招募一个单独的、独立的复制SAH队列用于该生物标记物的前瞻性验证。作为MIR 可能在网络中发挥作用，我们将探索全球血液miR转录组在患者亚群中的识别 可能的miR网络与SAH结局和DCI有关。为了检验miR-的生物学可信性 在定义SAH中一种新的炎症内型时，我们将探讨血液miR-26a与 临床全身性炎症反应综合征及其变化的表达和后续表现 血液中炎性细胞因子水平。

PROJECT SUMMARY Aneurysmal subarachnoid hemorrhage (SAH) is disproportionately lethal and morbid for young patients, causes extensive long-term disability, and results in significant health-economic burden to society. SAH is a heterogeneous condition. A unique feature of SAH is that, in addition to brain injury, patients can develop an acute and severe systemic illness with multiple extra-cerebral organ dysfunctions and a systemic inflammatory response syndrome. Several recent SAH clinical trials all failed to show therapeutic benefit partly due to the high degree of disease heterogeneity. A major barrier to a therapeutic breakthrough in SAH is the lack of appropriate biomarkers to identify patients most at risk for subsequent injury, complications, and bad outcome in this heterogenous population. Endotypes are biological subtypes defined by distinct pathophysiologic mechanisms that could be identified by corresponding biomarkers. Discovery of novel endotypes has led to major therapeutic breakthroughs in cancer and autoimmune diseases. MicroRNAs (miRs) are a novel class of molecules with ideal characteristics as potential biomarkers for systemic response to SAH because miRs are very stable in blood, very specific in their cells of origin and destination, can modulate biological processes in recipient cells by regulating gene expression, and are known to mediate inflammation and immune function. We have promising preliminary data showing that early increase in blood miR-26a after SAH is associated with favorable long-term outcome and possibly reduced risk for delayed cerebral ischemia (DCI), a major cause of morbidity. We hypothesize that blood miR-26a is an early biomarker for SAH long-term outcome and that miR-26a may modulate systemic inflammatory host response and reduce delayed cerebral ischemia (DCI). We propose to investigate miR-26a as a potential biomarker in an existing SAH patient cohort and biobank while simultaneously recruiting a separate, independent replication SAH cohort for prospective validation of this biomarker. As miRs may function in networks, we will explore the global blood miR transcriptome in a subset of patients to identify possible miR networks associated with SAH outcome and with DCI. To examine biological plausibility of miR- 26a in defining a novel inflammation endotype in SAH, we will explore the relationship between blood miR-26a expression and subsequent manifestations of clinical systemic inflammatory response syndrome and changes in blood inflammatory cytokine levels.