(provided by candidate): The long-term objective of this Scientist Development Award for New Minority Faculty is to prepare the candidate for a career as an independent investigator conducting preclinical and clinical research in the area of signal transduction as it relates to neuroendocrine-immune interactions in mood disorders. The training plan consists of an extensive curriculum of formal graduate level courses in psychoneuroimmunology, endocrinology, biostatistics, research methodology and ethical conduct in research. The candidate's research plan will focus on interactions between the neuroendocrine and immune systems, specifically, glucocorticoid and proinflammatory cytokine signal transduction pathways as they relate to the development of glucocorticoid resistance and the pathophysiology of mood disorders.
Specific aims i nclude 1) To determine the signal transduction pathways responsible for IL-1-induced impairment in glucocorticoid receptor (GR) function, 2) To examine the role of protein kinase A (PKA) in modulating IL-1-induced GR impairment, and 3) To determine whether chronic cytokine exposure in humans is associated with the development of impaired GR function. To accomplish these aims, the candidate will use cultured cell lines and primary human cells to investigate the role of mitogen-activated protein kinase (MAPK) pathways and protein-protein interactions (i.e., NF-B or AP-1 and GR mutual suppression) in IL-1-induced impairment of GR function. Given the capacity of PKA to enhance GR function and inhibit MAPK pathways, the candidate will also investigate the role of cAMP/PKA in restoring and enhancing GR function in the presence of IL-1. Finally, to support the hypothesis that chronic cytokine exposure leads to glucocorticoid resistance, blood samples will be obtained from 100 patients receiving interferon treatment for hepatitis C and in vitro glucocorticoid sensitivity of peripheral blood mononuclear cells (PBMC) will be determined. Results from this in vitro assay will be correlated with circulating and CSF concentrations of proinflammatory cytokines as well as the development of depression. In combining his expertise in steroid receptor signal transduction, his laboratory skills in basic cellular and molecular biology and solid clinical training, the candidate will be in a position to develop this award into an application for an independent research award over the 5-year award period. Moreover, insights gained from the proposed research will contribute to the development of novel therapeutic targets for the treatment of mood disorders. ? ?
| Hu, F; Wang, X; Pace, T W W et al. (2005) Inhibition of COX-2 by celecoxib enhances glucocorticoid receptor function. Mol Psychiatry 10:426-8 |
| Wang, Xiaohong; Wu, Huixia; Lakdawala, Viraj S et al. (2005) Inhibition of Jun N-terminal kinase (JNK) enhances glucocorticoid receptor-mediated function in mouse hippocampal HT22 cells. Neuropsychopharmacology 30:242-9 |
