The training and research components of this Research Career Development Award application are designed to prepare the applicant for a career as an independent investigator in the area of mind-body interactions. The long-term objectives are to examine bi-directional relationships between the hypothalamic-pituitary-adrenal (HPA) axis and the immune system and determine the effect of these interactions on the regulation of mood and related neurovegetative functions in medically ill patients. The applicant will devote the 5-year K23 project period to combining his expertise in clinical diagnosis and treatment with rigorous training in neuroimmunology and neuroendocrinology, as well as in research methodology, data organization, biostatistics, and the ethical conduct of research. The training program will consist of an integrated curriculum of formal didactic course work and tutorials with the sponsor and other consultants. The applicant's immediate research goal during the award period will be to examine the relationship between immune system activation and glucocorticoid resistance in patients who develop depressive symptoms during treatment with interferon (IFN)-alpha for chronic hepatitis C virus (HCV) infection. The hypotheses to be tested are as follows: 1) Chronic treatment with IFN-alpha will induce resistance to the inhibitory effects of endogenous glucocorticoids leading to unrestrained release of corticotropin-releasing hormone (CR1-I) and proinflammatory cytokines in the CNS, which in turn will lead to depressive symptoms and 2) Impaired glucocorticoid feedback inhibition at baseline (prior to IFN-alpha treatment) will predict depressive symptoms as a result of relatively unrestrained immune system activation and release of CRH during IFN-alpha therapy. To test these hypotheses, the following specific aims are proposed: 1) To measure concentrations of the proinflammatory cytokines interleukin (IL)-l, IL-6 and tumor necrosis factor-alpha (TNF-alpha), and CRH in cerebrospinal fluid (CSF) of 100 patients with HCV, randomized to receive IFN-alpha treatment or to post-pone treatment until study completion, 2) To determine the correlation among CSF concentrations of proinflammatory cytokines and CRH and behavioral endpoints in these patients, and 3) To explore the effect of chronic IFN-alpha treatment on sensitivity to glucocorticoid-mediated inhibition and to determine the relationship between glucocorticoid-mediated negative feedback and concentrations of IL-1, IL-6, TMF-alpha and CRH in CSF of IFN-alpha-treated patients. All subjects will undergo in vivo and in vitro assessment of sensitivity to glucocorticoid inhibition of the HPA axis and immune system at baseline (prior to beginning IFN-alpha for subjects randomized to active treatment) and again one month later. At study week 12, subjects will receive a lumbar puncture to measure CSF concentrations of CRH, arginine vasopressin and proinflammatory cytokines. Results from this study will enable further understanding of the pathways by which mood disorders arise out of conditions of immune activation and will provide the foundation for the development of novel strategies to treat depression in the medically ill.
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