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

aSAH 后中枢神经系统中的性类固醇和 IGF1 及其与患者预后的关系

• 批准号: 9789373
• 负责人: Elizabeth A Crago
• 金额: $ 53.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789373
• 关键词: Address; Affect; Anabolism; Androstenedione; Aneurysm; Aneurysmal Subarachnoid Hemorrhages; Aromatase; Attention; Binding; Biological; Biological Markers; Blood Vessels; Brain hemorrhage; Candidate Disease Gene; Cell Survival; Cerebral Ischemia; Cerebrospinal Fluid; Cerebrovascular Spasm; Cessation of life; Complex; Custom; DNA; Data; Development; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Equilibrium; Estradiol; Estrogens; Estrone; Fatigue; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Gonadal Steroid Hormones; Hormones; Hour; Human; Individual; Inflammation; Injury; Intervention; Ischemic Brain Injury; Language; Lead; Link; Liquid Chromatography; Literature; Measures; Mediating; Mediator of activation protein; Mental Depression; Modeling; Molecular; Moods; Nervous System Trauma; Neuraxis; Neurocognitive Deficit; Neuroglia; Neurologic; Neurons; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Peripheral; Persons; Phenotype; Physical Function; Plasma; Production; Property; Psyche structure; Publishing; Regulation; Research; Research Personnel; Risk; Role; Sampling; Signal Transduction; Somatomedins; Specimen; Stroke; Techniques; Testosterone; United States; Vasodilation; Visuospatial; Work; base; biobank; cell type; cohort; disability; evidence base; executive function; experience; flexibility; functional outcomes; genetic predictors; improved; improved outcome; innovation; mortality; neuroprotection; neurovascular unit; peptide hormone; personalized intervention; receptor; repaired; response; response to brain injury; tandem mass spectrometry; virtual

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.

项目摘要 动脉瘤性蛛网膜下腔出血（aSAH）是一种毁灭性的神经损伤， 占中风相关死亡的25%以上。aSAH后的生存通常很复杂 迟发性脑缺血（DCI）和长期残疾的发展。虽然 动脉瘤修复技术已得到改善，不良结局或干预的风险预测因素 但仍难以取得实质性改善成果。 根据文献和我们的初步数据，我们认为性类固醇 是神经损伤（包括aSAH）后有前途的生物标志物，但在 了解它们在人类病理生理学和结果中的个体和集体作用， 特别是在aSAH之后。性类固醇控制局部炎症，介导血管舒张， 是已知的细胞存活的分子调节剂。IGF 1是一种肽类激素， 生存信号几乎存在于每一种细胞类型中，包括神经元、神经胶质和微血管。 神经血管单位，并已链接到雌激素介导的神经保护。生物标志 浓度和生物活性受遗传倾向的影响。我们将其 aSAH后性类固醇的神经保护特性依赖于一种复杂的平衡， 性类固醇，IGF 1和遗传因素之间的联系-以前没有被发现 研究了该项目的目标是更好地确定（1）生物 aSAH后中枢神经系统中性类固醇和IGF 1的基础和（2） 他们与患者结果的关系。 我们非常成功的研究团队将利用一个良好的特点和纵向 536例aSAH患者的表型队列，DNA、血浆和脑脊液（CSF）相关 可从现有aSAH生物储存库获得的样品，以：1）检查 在aSAH后的前14天内，性类固醇和IGF 1浓度之间存在差异， DCI的发展以及3个月和12个月的患者结局; 2）检查血浆 预测CSF中指示大脑对损伤的反应的生物标志物水平， CSF获取;和3）确定特异于CSF的候选基因中的多态性的能力。 性类固醇和IGF 1生物合成途径，以区分有DCI风险的患者和 aSAH后3个月和12个月的结局。横截面和轨迹模型将 由每日aSAH血浆和CSF性类固醇水平产生（即，E2，E1，睾酮和 雄烯二酮）和IGF 1 通过ELISA测量浓度。定制iPLEX MassArray平台将用于 检测参与性类固醇和IGF 1生物合成途径的候选基因。 这项拟议研究的结果将（1）导致更好地确定生物 aSAH后患者结局变异性的基础和机制，（2）确定稳定的 不利结果（即死亡和残疾）的遗传预测因子，以及（3）告知 发展基于证据的个性化干预（例如，受体调节剂）， 减轻aSAH的负担和后果。