This K24 application seeks support for Steven Levine, an active, mid-career, clinical neuroscientist and neurologist with independent research support, involved in patient-oriented research. With this support, Dr. Levine can achieve, with greater focus, his long-term career goal of advancing knowledge of the significance of antiphospholipid-protein antibodies (aPL-P) (the most commonly identified hematologic mechanism of ischemic stroke) through research in ischemic cerebrovascular disease. He will use this support to enhance a nationally recognized, integrated, and collaborative clinical research program, provide critical time to serve as a mentor for beginning clinical investigators, and enhance his didactic knowledge base through structured coursework. This 5-year proposal will focus on (1) the role of aPL-P titer, and isotype in predicting recurrent stroke and death in a large cohort of ischemic stroke patients, and (2) the relative prognostic importance and significance of different types of coagulation tests for the lupus anticoagulant (one type of aPL-P) and more novel aPL-P, such as antibodies to 2 glycoprotein-I and antiphosphatidylserine antibodies. Multivariate models will be built to better define the predictive ability of each aPL-P, their isotype, and their titer for recurrent thrombo-occlusive events. (3) The role of aPL-P, thrombin-antithrombin complexes, tissue plasminogen activator antigen levels, and thrombomodulin in predicting treatment response, outcome, and intracerebral hemorrhage risk in the NINDS rt-PA Stroke Trial will also be investigated. This will allow aPL-P data from a large acute stroke trial to be compared and contrasted to a large stroke prevent on trial. (4) Pilot studies will be conducted, as well in the application of telemedicine for stroke (""""""""Telestroke""""""""). The applicant will also enroll in formal coursework aimed at increasing his knowledge and skill level concerning epidemiology, biostatistics, including sophisticated data analyses techniques, and immunology. This intensive research focus will allow the applicant to provide new insights and set new directions for further study of aPL-P and hemostatic markers in acute ischemic stroke patients who receive thrombolytic therapy, and in stroke patients receiving either anticoagulant or antiplatelet therapy, as well as allow him time to initiate new studies of telemedicine for stroke. This award will also allow him to mentor trainees (beginning clinicians and clinical investigators) within a comprehensive stroke program, using the (1) largest database to date of aPL-P positive stroke patients who have been systematically evaluated, prospectively followed, (2) the NINDS rt-PA Stroke Trial database, and (3) the trainee's independent research projects. Given the rapid exponential growth of insights into cerebrovascular disease, from molecular and genetic mechanisms to large-scale epidemiological and clinical trials, there is a critical and unmet need for formally trained clinical investigators to tackle the increasing frequency and burden of stroke in America.
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