This inpatient and outpatient General Clinical Research Center (GCRC) proposes to facilitate the transfer of basic knowledge generated in research laboratories to the clinical arena by elucidating pathogenic mechanisms of disease and evaluating new modes of patient management, and augment investigative collaborations among the clinicians and researchers at The Scripps Research Institute and Scripps Clinic. This application includes thirty-four research projects proposed for study on the Center. Among these protocols are studies to: (1) determine whether immunosuppression with 2-chlorodeoxyadenosine favorably alters the clinical course of relapsing and remitting multiple sclerosis, as it appears to do in patients with the chronic progressive form of this disease; (2) define mechanisms of thrombus formation through the study of platelet interactions with adhesive proteins (in particular, fibrinogen/fibrin, von Willebrand factor and collagen type I) under the influence of shear stress; (3) define the natural history and the response to enzyme replacement therapy in patients with genotypically different forms of Gaucher disease, and explore the possibility of gene replacement therapy in laboratory models; (4) examine the genetic and neurophysiological diversity in biological sensitivity to alcohol by comparing the electroencephalographic responses of low and high alcoholism risk patient populations to a standard alcohol challenge; (5) study the effect of aspirin treatment on the long-term course of ASA- sensitive asthmatics after aspirin desensitization, and analyze the expression and function of monocyte phospholipase A2 in ASA-sensitive subjects; (6) characterize the genetically determined mechanisms that establish the disease phenotype in patients with hereditary angioneurotic edema, analyze the molecular actions of 17alpha-alkylated androgens that are central to therapeutic efficacy, and the efficacy of C1 inhibitor therapy in this disease; (7) produce monoclonal antibodies that neutralize several important human pathogens (HIV-1, measles, herpes simplex, varcella, respiratory syncytial virus, etc.,) as a first step towards the development of antibody-based therapy of these infections; and (8) define the molecular and cellular characteristics of the hepatitis B virus specific cellular immune response during acute and chronic viral hepatitis, and to determine the role it plays in viral clearance and liver cell injury with the objective of developing viral epitope-based immunotherapies to terminate persistent HBV infection in patients with chronic hepatitis;. We anticipate that these and the remaining protocols contained in the application will lead to a greater understanding of disease mechanisms and to the eventual development of new preventive and therapeutic strategies to reduce the incidence and severity of human disease.
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