Serum markers of infection and inflammation have been associated with both incident myocardial infarction (Ml) and prognosis after Ml, but very little data about the relationship of these markers to stroke incidence or prognosis is available. Preliminary studies by the applicant have shown that chronic infection with Chlamydia pneumoniae (C. pneumoniae) is associated with stroke risk, and that elevated white blood cell count and soluble tumor necrosis factor receptor levels are associated with carotid atherosclerosis. The applicant has training in epidemiology, but no advanced training in laboratory techniques or in the basic biology of inflammation or infection. This career development award will train the applicant in the pathobiology of inflammation and infection, in basic techniques of molecular biology, and in advanced epiderniologic and biostatistical analysis. The proposed study will test the following hypotheses: 1) Elevated levels of markers of inflammation (CRP, interleukin 6, tumor necrosis factor receptor levels) and specific infections (C. pneumoniae, CMV) are independent predictors of first ischemic stroke, and 2) elevated levels of these markers of inflammation and infection are associated with worse prognosis after stroke. Two concurrent prospective study designs are proposed to test these hypotheses. For hypothesis 1, levels of these markers will be compared in 125 stroke cases and 250 controls, all of whom are drawn from the 3300 initially strokefree subjects in the Northern Manhattan Stroke Study (NOMASS, NINDS 2RO1-29993). ELISA will be used to measure marker levels. The blood samples analyzed will be those drawn at baseline, prior to stroke occurrence, using a strong design, the nested casecontrol study. Multiple conditional logistic regression analysis will be used to assess the significance of the main exposure variables after matching for age, gender, and race/ethnicity, and after adjustment for other risk factors. For hypothesis 2, 300 prospectively enrolled stroke patients in the Aortic Plaque and Risk of Ischemic Stroke Study (APRIS, NINDS R01-36286) will be followed up annually for 3 years for the occurrence of stroke, death, or Ml, and the levels of these markers in blood samples will be analyzed by ELISA. Cox proportional hazards modeling will be used to assess survival based on baseline inflammatory marker status after adjustment for other risk factors and stroke severity. The applicant will pursue coursework in infectious diseases and pathobiology of inflammation, as well as in advanced epidemiologic and biostatistical analysis. He will participate in laboratory practicums at Columbia and the CDC to gain handson knowledge of laboratory techniques, including ELISA and PCR, necessary for the present and future studies. It is anticipated that these experiences and the successful completion of the proposed project will allow him to compete for independent investigator awards. Nationally recognized experts in stroke epidemiology and basic vascular biology will serve as mentors for these studies.
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