GENETICS OF EARLY NEUROLOGICAL INSTABILITY AFTER ISCHEMIC STROKE (GENISIS)

中风是全世界第二大致死原因，也是导致长期残疾的首要原因。 缺血性中风是最常见的亚型，由大脑中的一条动脉闭塞引起，导致 神经功能障碍的突然发展。在中风发病后的最初几个小时内，神经缺陷可能 高度不稳定，许多患者病情好转，而另一些患者病情恶化。这些早期的变化有一个 对长期结果产生重大影响。事实上，在最初的24小时内，神经缺陷的变化可以解释 90d改良Rankin量表(最广泛接受的中风结局衡量标准)方差的40% 接受组织纤溶酶原激活剂(TPA)治疗的患者。在我的初步分析中发现， 基线临床因素在前24个月神经功能缺陷的变化中所占比例很小。 而遗传因素似乎占50%以上。鉴于这一发现，遗传学会影响 早期神经变化的变异，这是我的中心假设，遗传学在 确定急性缺血性中风(AIS)患者的早期预后。 作为一名接受过团契培训的急诊医生，专攻神经急救，我的长期 目标是开发一项独立的研究计划，以调查基因对急性胰腺炎的影响。 神经急救，以改善患者的预后。为了实现这个目标，我开发了 在获奖期间将实现的两个短期目标：1)熟练掌握技术 遗传/基因组分析和研究方法；2)更熟悉细胞 以及与AIS后脑和神经血管损伤有关的分子机制。为了 为了实现这些目标，我组建了一个由导师、顾问和合作者组成的多学科团队。超过了 在过去的几年里，我一直与我的主要导师李振武博士(主任)密切合作 脑血管疾病和神经重症监护科)和我的二级导师Dr。 Carlos Cruchaga(一位在复杂基因分析方面有专长的人类遗传学家)，研究可能的基因 急性缺血性卒中对早期神经学预后的影响。他们都有很好的记录 指导初级调查员，为我的指导和专业知识带来免费的背景和专业知识 职业发展。 在李振武博士和卡洛斯·克鲁查加博士的指导下，我将从事有组织的课程工作， 高级培训和独立学习，精通以患者为中心的研究，基因分析， 和研究方法。为了捕捉AIS后的早期神经变化，我们开发了一种新的 定量内表型，称为ΔNIHSS24，这是一种衡量NIH卒中评分变化的指标 (NIHSS)基线(发病后6小时)和24小时之间的评分。使用一组接受治疗的AIS患者 对于IV tPA，将由来自国际多中心联盟的3000名表型受试者组成 代表着世界上与遗传学有关的早期中风结果的最大此类数据集，我将探索 以下内容： 目标1：进行全基因组关联研究，检查早期神经变化 (ΔNIHSS 24小时)。使用首批3,000 tPA治疗的AIS患者(发现队列，估计收益 2016年9月)，将进行常见和稀有编码变体的GWA以发现单一变体， 与ΔNIHSS相关的基因和途径。另外3,000名接受tPA治疗的患者(复制 队列)将在2019年9月之前累加，并用于复制初始发现队列的结果。 目的2：使用大效应大小的低频函数变异的极端表型抽样 用于AIS后早期神经恶化(目标2a)或改善(目标2b)。我们会挑选病人 最极端的ΔNIHSS 24小时，代表那些恶化或改善最大的人，以及 与对照组比较，ΔNIHSS24小时无明显变化。在每个极端中复制最热门的歌曲将是 通过基于基因的测序和分析，在整个队列中执行。在那些病情恶化的患者中， 我们将确定哪些基因变异与出血性转化有关，哪些与出血转化无关。 这项研究计划体现了我在紧急情况下的多学科培训和职业发展 医学、神经急诊和遗传学。不偏不倚的做法是一个长期目标 这项研究提案将揭示与急性脑有关的重要变异、基因和途径 缺血，可能导致诊断和治疗目标，以改善中风后的预后。

Stroke is the 2nd leading cause of death throughout the world, and the leading cause of long-term disability. Ischemic stroke, the most common subtype, is caused by occlusion of an artery in the brain, resulting in the abrupt development of neurological deficits. In the first hours after stroke onset, neurological deficits can be highly unstable, with many patients improving while others deteriorate. These early changes have a major impact on long-term outcome. In fact, changes in neurologic deficits during the first 24 hours account for 40% of the variance of the 90-day modified Rankin Scale (the most widely accepted stroke outcome measure) in patients treated with tissue plasminogen activator (tPA). In my preliminary analyses, it was discovered that baseline clinical factors account for very little of the variation seen in neurologic deficits during the first 24 hours while genetic factors appear to account for over 50%. Given the finding that genetics influence the variance of early neurologic changes, it is my central hypothesis that genetics play a significant role in determining the early outcomes experienced by patients suffering from acute ischemic stroke (AIS). As a fellowship-trained emergency physician subspecializing in neurologic emergencies, my long term goal is to develop an independent research program to investigate genetic influences on acute neurological emergencies to improve patient outcomes. In order to achieve this goal, I have developed two short term goals that will be achieved during the award period: 1) to become technically proficient in genetic/genomic analysis and research methodology and 2) to develop greater familiarity with cellular and molecular mechanisms involved with brain and neurovascular injury following AIS. In order to achieve these goals, I have crafted a multidisciplinary team of mentors, advisors and collaborators. Over the past several years, I have been working closely with my primary mentor, Dr. Jin-Moo Lee (Director of the Cerebrovascular Disease and Neurointensive Care Sections in Neurology) and my secondary mentor Dr. Carlos Cruchaga (a human geneticist with expertise in complex genetic analyses), to examine possible genetic influences on the early neurologic outcomes after acute ischemic stroke. They both have a strong track record of mentoring junior investigators and bring complimentary backgrounds and expertise to my mentoring and career development. Under the guidance of Drs. Jin-Moo Lee and Carlos Cruchaga, I will engage in structured coursework, advanced training and independent study to become proficient in patient-oriented research, genetic analysis, and research methodology. To capture early neurological change following AIS, we have developed a novel quantitative endophenotype, termed ΔNIHSS24h, which is a measure of the change in NIH stroke scale (NIHSS) score between baseline (<6 hours after onset) and 24 hours. Using a cohort of AIS patients treated with IV tPA that will consist of 3,000 phenotyped subjects drawn from an international multicenter consortium and representing the largest such dataset of early stroke outcomes linked to genetics in the world, I will explore the following: Aim 1: To perform genome-wide association studies (GWAS), examining early neurological change (ΔNIHSS24h) after AIS. Using the first 3,000 tPA-treated AIS patients (Discovery cohort, estimated accrual September, 2016), GWAS of common & rare coding variants will be performed to discover single variants, genes, and pathways associated with ΔNIHSS24h. An additional 3,000 tPA-treated patients (Replication Cohort) will be accrued by September 2019, and used to replicate findings from the initial Discovery cohort. Aim 2: To use extreme phenotype sampling with low frequency functional variants of large effect size for early neurological deterioration (Aim 2a) or improvement (Aim 2b) after AIS. We will select patients with the most extremes of ΔNIHSS24h, representing those with greatest deterioration or improvement, and compare to matched controls with little change in ΔNIHSS24h. Replication of the top hits in each extreme will be performed in the overall cohort with gene-based sequencing and analysis. Of those patients who deteriorate, we will determine which genetic variants associate with hemorrhagic transformation and which do not. This research plan reflects my multidisciplinary training and career development in emergency medicine, neurologic emergencies, and genetics. It is a long-term objective that the unbiased approach presented in this research proposal will reveal important variants, genes and pathways involved in acute brain ischemia, possibly leading to both diagnostic and therapeutic targets to improve outcomes following stroke.