The GCRC serves a the core clinical research facility for clinical investigators at New England Medical Center Hospital and Tufts University School of Medicine. The Center has been in continuous operation since 1961, and supports the conduct of clinical research protocols based on evaluation of scientific merit by the multidisciplinary Scientific Advisory Committee. The eight major proposals contained in the present application represent a diversity of scientific and medical disciplines, combining excellence in clinical investigation with links of mechanistic basic science work and application of novel biomedical technologies. These core proposals are: 1. Evaluation of the molecular basis for ethnic differences in lipoprotein metabolism, and the implications of these differences for differential susceptibility to cardiovascular disease (Dr. Ernst J. Schaefer); 2. Evaluation of the mechanisms of bronchopulmonary dysplasia in neonates with respiratory distress syndrome, and the therapeutic potential of inhaled beclomethasone (Dr. Ivan D. Frantz); 3. Mechanisms and implications of systemic cytokine response in the pathogenesis of primary biliary cirrhosis, and modulation following treatment with colchicine, methotrexate, or ursodeoxycholic acid (Drs. Marshall M. Kaplan and David J. Wyler); 4. Initial evaluation of """"""""gene therapy"""""""" technology in the treatment of cystic fibrosis. The study will assess the response to topical pulmonary administration of a virus vector designed to express the deficient cystic fibrosis transmembrane conductance regulator protein, the lack of which is the basis for the pathogenesis of cystic fibrosis (Dr. Henry L. Dorkin); 5. Evaluation of the biochemical mechanisms of the cachexia of chronic disease in patients with rheumatoid arthritis, and modulation of biochemical markers in response to treatment (Dr. Ronenn Roubenoff); 6. Prospective validation of a scaling model designed to predict the qualitative and quantitative inhibition of Cytochrome P450- mediated hepatic clearance of drugs by competitive metabolic inhibitors, based on in vitro studies of enzyme kinetics using human liver microsomes. The index compound is midazolam, a P450-3A4 substrate, and the model competitive inhibitor in the azole antifungal agent ketoconazole (Dr. David J. Greenblatt); 7. Comprehensive prospective evaluation of the impact of HIV infection on body composition, nutritional status, gastrointestinal function, protein metabolism, and cytokine function. These outcomes, including response to dietary and exercise interventions, are prospectively studies in populations of HIV-infected individuals and matched controls (Dr. Sherwood L. Gorbach); 8. Modulation of the systemic toxicity of Interleukin-2 by coadministration of soluble Interleukin-1 receptor in patients with metastatic cancer. The study involves clinical assessments of response and toxicity as well as evaluation of alterations in multiple biologic parameters (Dr. Michael B. Atkins).
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