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Andrew H Miller, M.D.

Research Interests

Short Description: Glucocorticoids as mediators of interactions between the CNS and the immune system.

Long Description: Laboratory Interests: Work in Dr. Miller's laboratory addresses the role of the immune system in psychiatric disorders, in particular the potential contribution of the immune system to the pathophysiology of psychiatric disease. Of particular interest are Dr. Miller's recent studies demonstrating the impact of cytokines (and antidepressants) on the expression and function of glucocorticoid receptors. Research Projects: Projects in the laboratory include examination of: 1) The effects of viral infection on the neuroendocrine system of mice. The goals of this project are to determine through what pathways the immune system accesses the endocrine system during viral infection and to determine what the consequences are. We have already shown that interleukin (IL)-6 is the pivotal cytokine for activating the hypothalamic-pituitary-adrenal (HPA) axis in murine cytomegalovirus infection (MCMV) and that the related glucocorticoid response to MCMV is necessary to prevent death following viral infection. If glucocorticoids are blocked, death occurs in MCMV through tumor necrosis factor (TNF)-alpha. We are now examining whether IL-6 activates the HPA axis during MCMV infection through activation of corticotropin releasing factor (CRF). We will also examine what cytokines are involved in CRF activation in the brain (if CRF activation occurs) and what behavioral consequences occur as a result of brain CRF activation. We are employing CRFKO mice and IL-6K0 mice for these studies. 2) Effects of Interferon (IFN) alpha on the neuroendocrine system and behavior of humans. The goal of this project is to apply knowledge gained from our mouse viral studies to understand the mechanism behind the behavioral toxicity observed in patients receiving high dose interferon alpha therapy for malignant melanoma or hepatitis C. IFN-alpha is an important early cytokine in viral infection, and patients receiving IFN-alpha exhibit a high rate of depression. They also show marked activation of IL-6 and the HPA axis. We believe that IL-6 is responsible for glucocorticoid induction during IFN-alpha treatment but that TNF (like in the mouse model) is responsible for the behavioral toxicity. We have access to behavioral measures as well as serum and cells from these patients. We are also using antidepressants as preventative therapy but plan to devise more targeted strategies based on future studies. All results gained from this project may be relevant to depressed patients as a whole, especially those with medical disorders associated with increased release of proinflammatory cytokines. 3) Effects of cytokines and antidepressants on glucocorticoid receptor (GR) function. The impact of cytokines on glucocorticoid receptors may play an important role in the mechanism by which cytokines mediate neurotoxicity. We have recently shown that IL-1 can block the translocation of the GR. Since glucocorticoids serve to feedback negatively on proinflammatory cytokines, impaired GR function as mediated by IL-1 might allow cytokines like TNF to come out from under glucocorticoid control. TNF in turn may mediate neurotoxicity as noted above. Depressed patients exhibit glucocorticoid resistance, and we are investigating the molecular mechanisms for this, possibly converging with pathways involved in the IL-1 effect on GR function (i.e., heat shock proteins). Techniques: Dr. Miller's laboratory and animal facilities are fully equipped for immunological, virological, neuroendocrinological a

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Last Update: 08/02/2015