Determining Genetic and Biomarker Predictors of DCI and Long Term Outcomes after

确定 DCI 的遗传和生物标志物预测因素以及术后长期结果

• 批准号: 8118063
• 负责人: SAMUEL M POLOYAC
• 金额: $ 68.01万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118063
• 关键词: Acids; Affect; Age; Aneurysmal Subarachnoid Hemorrhages; Arachidonic Acids; Biological Markers; Blood Vessels; Cerebral Ischemia; Cerebrospinal Fluid; Clinical; Coupled; Data; Development; Discipline of Nursing; Early treatment; Endothelin-1; Enzyme Gene; Evaluation; Event; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Goals; Health; Hydroxyeicosatetraenoic Acids; Impairment; Intervention; Ion Channel; Ischemia; Lead; Measures; Mediating; Mediator of activation protein; Methods; Occupational; Outcome; Pathway interactions; Patients; Persons; Production; Public Health; Recruitment Activity; Research; Role; Sampling; Science; Subarachnoid Hemorrhage; Therapeutic Intervention; Variant; Vasoconstrictor Agents; Vasospasm; Work; base; cerebrovascular; experience; follow up assessment; genetic analysis; genetic variant; high risk; improved; neuropsychological; patient population; predictive modeling; therapeutic target; therapy design

DESCRIPTION (provided by applicant): This is a competitive renewal of our two prior studies: "Methods of Predicting DCI in aSAH" (R01- NR004339-01), and "Role of 20-HETE on vasospasm-induced ischemia after aSAH" (R01NR004339-05). It is the long-term goal of this research to improve patient outcomes by utilizing biomarker-directed early- intervention strategies to reduce ischemic complications after aSAH. In the previous support period, our team identified key vasoactive metabolites, ET-1 and 20-HETE, which were predictive of cerebrovascular complications and long term outcomes. As the logical extension of this work, we propose to examine the key gene variants that regulate the production, degradation, and ion channel effects of these metabolites as they relate to DCI and neuropsychological outcomes. We hypothesize that variants in biomarker pathway genes will significantly contribute to the variability in biomarker concentrations, complications, and outcomes after aSAH. The specific aims of this proposal are to determine the relationship between elevated cerebrospinal fluid (CSF) biomarkers (ET-1, 20-HETE, and EETs) and specific gene variants that lead to variation in their production and/or degradation; to examine the direct and mediated effects of gene variants in ET-1, 20-HETE, and EET pathways through CSF biomarkers on DCI, and to examine the direct and mediated effects of gene variants in ET-1, 20-HETE, and EET pathways through CSF biomarkers on functional and neuropsychological (NP) outcomes. We will recruit 192 patients with SAH (ages 18-75 years) in order to achieve a final sample of 145 patients available at twelve month follow up assessment. These subjects coupled with the 372 patients recruited to date will allow for the identification of the key genetic variants and the mediating effects of biomarker concentrations on DCI and NP outcomes. Elucidation of these relationships will allow for future development and evaluation of predictive models for identification of patients at high risk for cerebrovascular complications and poor outcomes after aSAH, thereby, allowing for directed intervention strategies to improve outcomes in this highly heterogeneous, understudied patient population. PUBLIC HEALTH RELEVANCE: Data from the proposed study, currently unexplored in persons with aneurysmal subarachnoid hemorrhage, will impact public health by serving as the basis for both therapeutic interventions designed to decrease the cascade of events that ultimately result in delayed cerebral ischemia and interventions to help patients compensate for long term deficiencies in physical and neuropsychological function.

描述（由申请人提供）：这是我们先前的两项研究的竞争性更新：“预测ASAH中的DCI的方法”（R01- NR004339-01），“ 20-Hete在血管痉挛诱导的缺血后的作用”（R01NR004339-05）。这项研究的长期目标是利用生物标志物指导的早期干预策略来减少ASAH之后的缺血并发症，从而改善患者的预后。在上一个支持期间，我们的团队确定了关键的血管活性代谢产物ET-1和20-HETE，这些代谢物可预测脑血管并发症和长期结局。作为这项工作的逻辑扩展，我们建议研究这些代谢产物与DCI和神经心理学结果相关的关键基因变体。我们假设生物标志物途径基因的变异将显着导致生物标志物浓度，并发症和ASAH之后的结果的变异性。该提案的具体目的是确定脑脊液升高（CSF）生物标志物（ET-1，20-HETE和EET）与特定基因变异之间的关系，从而导致其生产和/或降解的变化；为了检查基因变异在ET-1，20-HETE和EET途径中通过CSF生物标志物在DCI上的直接和介导的作用，并检查基因变异物在ET-1，20-HETE和EET途径中通过CSF生物标志物对功能和神经心理学（NP）的直接和中介作用。我们将招募192名SAH（18-75岁）患者，以便在十二个月的随访评估中获得最终样本。这些受试者以及迄今为止招募的372名患者将允许鉴定关键遗传变异体以及生物标志物浓度对DCI和NP结果的中介作用。阐明这些关系将允许对未来的开发和评估预测模型，以鉴定脑血管并发症高风险的患者和近视后的不良预后，从而允许定向干预策略以改善这种高度异质，研究的患者人群的结果。公共卫生相关性：拟议研究的数据目前尚未在动脉瘤亚蛛网膜下腔出血的人中探索，将通过作为旨在减少旨在减少脑缺血性延迟的长期降低性延迟的身体延迟的治疗措施的治疗干预措施的基础来影响公共卫生。