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（由适用提供）：瞬态缺血性攻击（TIA）对于识别至关重要，因为预防疗法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天内中风。由于如此多的患者紧急出现短暂的神经事件，因此大多数人没有继续进行中风，因此识别中风高风险的TIA的方法一直在暗示，因此工作和治疗可以针对那些最需要的人来节省时间，金钱和有限的资源。尽管ABCD2评分和大脑扩散加权成像-MRI（DWI-MRI）的预测提高了TIA的中风的预测，但它们对预测我差的个体病例的敏感性和特异性。在这一建议中，我们建议外周血白细胞和血小板扮演着关键作用，其中TIAS继续中风并通过评估全血中的RNA，我们可以评估白细胞和血小板功能，而TIA患者的中风与没有中风的患者可以评估白细胞和血小板功能。我们假设在TIA患者中激活了特定的凝血和免疫原，与那些在90天之前没有中风的TIA患者相比，使他们倾向于90天的中风。这些白细胞和血小板mRNA基因的一部分将预测90天的中风的TIA。以下特定目的解决了这一假设。 AIM＃1（衍生队列）：证明，与那些在90天之前没有中风的TIA相比，使用RNASEQ从全血的RNASEQ中测得的mRNA表达，这些tias的衍生物差异差异。证明大多数使用RNASEQ调节的mRNA在使用QRT-PCR进行测量时也会显着调节。 AIM＃2（派生队列）：将机器学习算法从AIM＃1应用于mRNA，以得出由RNASEQ和QRT-PCR调节的最佳mRNA子集，该子集可预测哪些TIA的中风在90天中与那些在交叉差异中> 95％灵敏度相比，该tias的中风为90天。 AIM＃3（验证队列）：使用机器/预测学习算法来证明AIM＃2使用QRT-PCR在独立验证队列上测量的AIM 2的基因预测哪些TIA的中风在90天之前且灵敏度> 85％。这些研究的目的是发现血液中的mRNA特征，以预测哪些TIA患者在90天之前继续遇到中风。当在以后的研究中确认，这将在深度测试中进行最需要的高风险TIA，以防止中风，并减少中风风险低的人的不必要的测试。同样重要的是，发现与TIA患者中风的高风险相关的基因将代表潜在的新型中风预防靶标。