I have developed my interest in molecular biology by working in several laboratories, where I have studied the biochemistry of transcription, molecular genetics of thalassemia, and molecular endocrinology. These experiences have molded my thinking as a scientist, and provided a framework for understanding the application of advances in basic science to clinical medicine. During my residency in Internal Medicine, I became interested in the pathogenesis of the rheumatic diseases. The proposed project will allow me to apply state of the art techniques and approaches of molecular biology to unravel molecular mechanisms which underly immune activation and synovial proliferation in autoimmune disease. Activation of B and T lymphocytes, and the accompanying induction of class II major histocompatibility (MHC) and interleukin-2 (IL-2) genes, are prominent features of autoimmunity. Aberrant synovial class II expression and proliferation are found in rheumatoid arthritis. We have cloned the cDNA and characterized a transcription factor, mXBP, which binds to the X box transcription element in the murine A-alpha class II MHC gene. mXBP interacts with and alters the DNA binding properties of proto-oncogene products Fos and Jun, which play a role in IL-2 gene induction and lymphocyte activation. Initially, we will characterize the role of mXBP in class II gene expression by overexpressing mXBP, and dominant negative mutants of mXBP, in lymphoid cells and stimulating with agents known to regulate class II. We will use similar approaches to examine the effect of the mXBP-Jun interaction on IL-2 gene expression. To extend this analysis to study lymphocyte activation, we will make transgenic mice which overexpress mXBP (or dominant negative mutants) in lymphocytes. We expect these mice to have an immunodeficient or hyper-reactive/autoimmune phenotype, and will characterize their immune responses. Finally, we will analyze the role of mXBP in synoviocyte class II and collagenase gene expression. These studies may reveal a central target for therapeutic intervention in autoimmune disease. Dr. Glimcher's laboratory has expertise in all techniques needed for this project and has made significant contributions in characterizing transcription factors and understanding class II regulation. Her laboratory is situated in a large medical center with excellent programs in immunology, molecular biology, and rheumatology, and should provide an optimal environment in which to achieve my outlined goals.
| Ivashkiv, L B; Schmitt, E M; Castro, A (1996) Inhibition of transcription factor Stat1 activity in mononuclear cell cultures and T cells by the cyclic AMP signaling pathway. J Immunol 157:1415-21 |
| Wang, F; Sengupta, T K; Zhong, Z et al. (1995) Regulation of the balance of cytokine production and the signal transducer and activator of transcription (STAT) transcription factor activity by cytokines and inflammatory synovial fluids. J Exp Med 182:1825-31 |
| Ivashkiv, L B; Ayres, A; Glimcher, L H (1994) Inhibition of IFN-gamma induction of class II MHC genes by cAMP and prostaglandins. Immunopharmacology 27:67-77 |
| Ivashkiv, L B; Fleming, M D; Glimcher, L H (1992) Dominant negative mutants of transcription factor mXBP (CRE-BP1, ATF-2). New Biol 4:360-8 |
| Ivashkiv, L B; Glimcher, L H (1991) Repression of class II major histocompatibility complex genes by cyclic AMP is mediated by conserved promoter elements. J Exp Med 174:1583-92 |
