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 o...