Sex Steroids and IGF1 in the CNS Following aSAH and Their Relationship to Patient Outcomes

项目总结 动脉瘤性蛛网膜下腔出血(ASAH)是一种毁灭性的神经系统疾病， 占中风相关死亡人数的25%以上。ASAH后的生存通常是复杂的 通过迟发性脑缺血(DCI)和长期残疾的发展。虽然 动脉瘤修复技术得到了改善，预示着不良结局或干预措施的风险 实质性改善的结果仍然难以捉摸。 根据文献中的证据和我们的初步数据，我们认为性类固醇 是包括ASAH在内的神经损伤后很有希望的生物标记物，但在 了解它们在人类病理生理学和结局中的个体和集体作用， 特别是在阿萨赫之后。性激素控制局部炎症，调节血管扩张和 是已知的细胞存活的分子调节因子。IGF1是一种多肽荷尔蒙，它能在体内发挥促胰岛素释放作用。 几乎每种细胞类型中的生存信号，包括神经元、神经胶质细胞和微血管 神经血管单位，已被认为与雌激素介导的神经保护有关。生物标志物 浓度和生物活性受遗传易感性的影响。我们假设 ASAH后性激素的神经保护作用依赖于复杂的平衡 性激素、IGF1和遗传因素之间的联系--这是以前没有过的联系 调查过了。该项目的目标是更好地确定(1)生物 ASAH和(2)后性激素和IGF1在中枢神经系统的基础 它们与患者预后的关系。 我们非常成功的研究团队将利用具有良好特点的纵向 536例DNA、血浆和脑脊液连锁的ASAH患者的表型队列 可从现有ASAH生物存储库获得的样本用于：1)检查关系 ASAH后14天内性激素和IGF1浓度之间的关系 DCI的发展和3个月和12个月的患者预后；2)检测血浆 预测脑脊液中指示脑损伤反应的生物标志物水平 脑脊液获取；以及3)确定候选基因中特定于 性激素和IGF1生物合成途径在区分DCI高危患者和贫困患者中的作用 ASAH后3个月和12个月的结果。横截面和弹道模型将 从每天的ASAH血浆和脑脊液中产生的性类固醇水平(即E_2、E_1、睾酮和 雄烯二酮(雄烯二酮)的液相色谱-串联质谱法和IGF1测定 用酶联免疫吸附试验测定血药浓度。自定义IPLEX Massarray平台将用于 检验性类固醇和IGF1生物合成途径中的候选基因。 这项拟议研究的结果将(1)导致更好的生物测定 ASAH后患者预后变化的基础和机制，(2)确定稳定性 不良结局的遗传预测因素(即死亡和残疾)，以及(3)告知 开发基于证据的个性化干预措施(例如，受体调节剂)以 减轻ASAH的负担和后果。

PROJECT SUMMARY Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating neurologic insult that accounts for more than 25% of stroke related deaths. Survival after aSAH is often complicated by the development of delayed cerebral ischemia (DCI) and long term disability. Although aneurysm repair techniques have improved, predictors of risk for poor outcomes or interventions that substantially improve outcomes remain elusive. Based on evidence from the literature and our preliminary data, we believe that sex steroids are promising biomarkers following neurological injury including aSAH, but there is a gap in understanding their individual and collective roles in pathophysiology and outcome in humans, specifically following aSAH. Sex steroids control local inflammation, mediate vasodilation and are known molecular regulators of cell survival. IGF1 is a peptide hormone that exerts pro- survival signals in virtually every cell type, including the neurons, glia, and micro-vessels of the neurovascular unit and has been linked to estrogen mediated neuroprotection. Biomarker concentration and bioactivity are influenced by genetic predisposition. We posit that neuroprotective properties of sex steroids following aSAH depend on a complex balance between sex steroids, IGF1, and genetic factors - linkages that previously have not been investigated. The goal of this proposed project is to better determine (1) the biological underpinnings of sex steroids and IGF1 in the central nervous system following aSAH and (2) their relationships with patient outcomes. Our highly successfully research team will utilize a well characterized and longitudinally phenotyped cohort of 536 aSAH patients with linked DNA, plasma and cerebrospinal fluid (CSF) samples which are available from an existing aSAH biorepository to: 1) examine the relationship between sex steroid and IGF1 concentrations during the first 14 days following aSAH to the development of DCI and 3- and 12-month patient outcomes; 2) examine the ability of plasma to predict CSF levels of biomarkers indicative of the brain's response to injury for patients without CSF access; and 3) determine the ability of polymorphisms in candidate genes specific to the sex steroid and IGF1 biosynthetic pathway to differentiate patients at risk for DCI and poor outcomes at 3- and 12-months following aSAH. Cross-sectional and trajectory models will be generated from daily aSAH plasma and CSF sex steroid levels (i.e., E2, E1, testosterone and androstenedione) measured by liquid chromatography-tandem mass spectrometry and IGF1 concentrations measured by ELISA. The Custom iPLEX MassArray platform will be used to examine candidate genes involved in the biosynthetic pathway of sex steroids and IGF1. Results from this proposed study will (1) lead to a better determination of the biologic underpinnings and mechanisms for variability in patient outcomes after aSAH, (2) identify stable genetic predictors of unfavorable outcomes (i.e. death and disability), and (3) inform the development of evidence-based personalized interventions (e.g., receptor modulators) to mitigate the burden and consequences of aSAH.