Whole Transcriptome Studies of Patients with Transient Ischemic Attacks (TIAs)

短暂性脑缺血发作 (TIA) 患者的全转录组研究

• 批准号: 9243329
• 负责人: FRANK R SHARP
• 金额: $ 57万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243329
• 关键词: Address; Algorithms; Alternative Splicing; Area; Arterial Fatty Streak; Atherosclerosis; Biological Markers; Blood; Blood Platelets; Blood Vessels; Brain; Cerebrum; Clinical; Coagulation Process; Data; Derivation procedure; Diagnosis; Diagnostic tests; Diffusion Magnetic Resonance Imaging; Emergency Situation; Epilepsy; Event; Exons; Future; Genes; Genetic Transcription; Goals; Hour; Immune; Individual; Ischemic Stroke; Labyrinthine disorder; Learning; Leukocytes; Machine Learning; Measures; Messenger RNA; Meta-Analysis; Methods; Migraine; Neurologic; Patients; Play; Prevention therapy; Publishing; Quantitative Reverse Transcriptase PCR; RNA; ROC Curve; Recurrence; Resources; Risk; Risk Estimate; Role; Sensitivity and Specificity; Site; Stroke; Stroke prevention; Symptoms; Testing; Therapeutic Intervention; Time; Transcript; Transient Ischemic Attack; Validation; Whole Blood; base; cohort; gene discovery; high risk; human subject; improved; mRNA Expression; monocyte; neutrophil; novel; peripheral blood; prospective; public health relevance; release factor; transcriptome; transcriptome sequencing

 DESCRIPTION (provided by applicant): Transient ischemic attacks (TIA) are critical to identify because prevention therapy can reduce the risk of future vascular events by > 50%. Diagnostic testing and therapeutic intervention must start as soon as possible because 10-25% of TIAs have a stroke within 90 days. Because so many patients present emergently with transient neurological events the large majority of whom do not go on to have a stroke, methods for identifying TIAs at high risk for stroke have been sought so that work up and treatment can be targeted to those who need it most to save time, money and limited resources. Though the ABCD2 score and brain Diffusion Weighted Imaging-MRI (DWI-MRI) have improved prediction of which TIAs have a stroke, their sensitivity and specificity for prediction of individual cases i poor. In this proposal we propose that peripheral blood leukocytes and platelets play pivotal roles in which TIAs go on to have a stroke and by assessing RNA in whole blood we can evaluate leukocyte and platelet function in TIA patients who go on to have stroke versus those that do not have a stroke. We hypothesize that specific coagulation and immune genes are activated in TIA patients that predispose them to have a stroke by 90 days compared to those TIA patients who do NOT have a stroke by 90 days. A subset of these leukocyte and platelet mRNA genes will predict TIAs who have a stroke by 90 days. This hypothesis is addressed by the following specific aims. Aim #1 (Derivation Cohort): Demonstrate that mRNA expression measured using RNAseq from whole blood differs in a derivation cohort of TIAs that go on to have a stroke by 90 days compared to those TIAs who do not have a stroke by 90 days. Demonstrate that most mRNA found to be regulated using RNAseq are also significantly regulated when measured using qRT-PCR. Aim #2 (Derivation Cohort): Apply machine learning algorithms to the mRNA from Aim #1 to derive an optimal subset of mRNA regulated by both RNAseq and qRT-PCR that predict which TIAs have strokes by 90 days compared to those who do not with >95% sensitivity on cross-validation. Aim #3 (Validation Cohort): Use machine/prediction learning algorithms to demonstrate that the genes from Aim #2 when measured using qRT-PCR on an independent validation cohort predict which TIAs have a stroke by 90 days with >85% sensitivity. The goal of these studies is to discover mRNA profiles in blood that predict which TIA patients go on to have strokes by 90 days. When confirmed in future studies, this will direct in depth testing to those high risk TIAs most in need in order to prevent strokes, and decrease unnecessary testing in those with low risk of stroke. Equally as important, the genes discovered to be associated with high risk of stroke in TIA patients will represent potential novel stroke prevention targets.

 描述（由申请人提供）：短暂性脑缺血发作（TIA）的识别至关重要，因为预防治疗可以将未来血管事件的风险降低> 50%。诊断测试和治疗干预必须尽快开始，因为10-25%的TIA在90天内发生中风。由于如此多的患者出现短暂的神经系统事件，其中绝大多数不会继续中风，因此一直在寻找识别中风高风险TIA的方法，以便工作和治疗可以针对最需要的人，以节省时间，金钱和有限的资源。虽然ABCD 2评分和脑弥散加权成像-MRI（DWI-MRI）提高了TIA发生卒中的预测能力，但其预测个体病例的敏感性和特异性较差。在该提案中，我们提出外周血白细胞和血小板在TIA继续发生卒中中起关键作用，并且通过评估全血中的RNA，我们可以评估TIA患者中继续发生卒中与未发生卒中的白细胞和血小板功能。我们假设TIA患者中特定的凝血和免疫基因被激活，与90天内未发生卒中的TIA患者相比，这些患者在90天内易患卒中。这些白细胞和血小板mRNA基因的子集将预测TIA谁有中风90天。这一假设通过以下具体目标得以解决。目的#1（衍生队列）：证明使用RNAseq从全血测量的mRNA表达在TIA的衍生队列中存在差异，这些TIA在90天内继续发生卒中，与那些在90天内未发生卒中的TIA相比。证明当使用qRT-PCR测量时，发现使用RNAseq调节的大多数mRNA也被显著调节。目标#2（衍生队列）：将机器学习算法应用于来自目标#1的mRNA，以衍生出由RNAseq和qRT-PCR两者调节的mRNA的最佳子集，其预测哪些TIA在90天前具有中风，与那些没有中风的TIA相比，交叉验证的灵敏度>95%。目标#3（验证队列）：使用机器/预测学习算法证明，当使用qRT-PCR对独立验证队列进行测量时，来自目标#2的基因预测哪些TIA在90天内发生卒中，灵敏度>85%。这些研究的目的是发现血液中的mRNA谱，预测哪些TIA患者在90天内会发生中风。当在未来的研究中得到证实时，这将指导对那些最需要的高风险TIA进行深入测试，以预防中风，并减少对那些中风风险低的患者进行不必要的测试。同样重要的是，在TIA患者中发现的与卒中高风险相关的基因将代表潜在的新的卒中预防靶点。