• Professor of Microbiology & Immunology
• Member of the Walther Oncology Center

• Campus Address: MS 420
• Telephone: (317) 274-2082
• E-mail: xfu@iupui.edu

Hal Broxmeyer named distinguished professor at IUSM (click here for more details)

Janice Blum discusses Immunology & Infectious Diseases (click here for more details)

Training:
• B. S. , 1982: Nanjing Normal University, China            
• M. A.,1983: Columbia University, New York
• M. Phil., 1985: Columbia University, New York              
• Ph. D., 1988: Columbia University, New York            
• Postdoctoral Training, 1988-1991: Rockefeller University

Description and summary of research focus of the laboratory:
We are focusing on studies of the STAT signaling pathway in regulation of inflammation, innate, adaptive immunity, development and body homeostasis.

Research projects in the laboratory:
a) Reveal molecular mechanisms of STAT proteins in regulation of immunity and inflammation. In particular, we will investigate how innate immunity is regulated through STAT3 and other signaling proteins. Furthermore, we will determine the roles of adaptive immune responses using the model system we have generated for the development of Crohn's disease phenotypes in the STAT3 deficient mice. One important question is whether Th1 cells are required for the chronic inflammation caused by STAT3 deletion in this Crohn's disease like syndrome. We will use mouse genetics by crossing STAT3 deficient mice with mice that are deficient in Th1 cell development, including STAT4 and STAT1 null mice and Toll-like Receptor 4 deficient mice. An attractive model is the STAT3 mediates a negative feedback loop that controls innate responses during mucosal immune tolerance. We will also investigate further the genes that are regulated by STAT3 that inhibit innate immunity. These studies should shed light on a novel aspect of innate immunity regulation and provide a new understanding of human inflammatory diseases involving innate immunity.  

b) Cytokines and inflammation have emerged as one of the most important factors involved in the development of chronicle congestive heart failure (CHF) . To study inflammation and its role in CHF, we will further develop and analyze animal models in molecular pathogenesis of CHF . In particular, we will use cardiac STAT3 KO model to establish the functional role of STAT3 in control of innate immune responses and inflammation in cardiac restricted tissues; to reveal molecular mechanisms by which expression of inflammatory cytokines are regulated by STAT3 in caridomyocytes, and why loss of STAT3 contributes to pathogenesis of CHF: we will further establish additional animal models to reveal roles of peripheral and systematic inflammation in development of cardiovascular disorders. To achieve this objective, we will use two unique strains of mice we have recently generated that have specific STAT3 deletion in endothelium and in bone marrow. To use these mice to generate systematic and/or peripheral inflammation and to study roles of circulating cytokines in development of CHF. These proposed experiments should provide important information on the mechanisms of the regulation of cardiovascular inflammation, on the molecular basis of pathogenesis associated with inflammatory cytokines and on factors that cause heart failure.

c) Autoimmune diseases are complex syndromes of self-destruction caused by disorders not only in adaptive immune responses but also in innate immune responses. The major cause of autoimmune disease is loss of immune tolerance. It is essential to reveal the molecular mechanisms by which immune tolerance is regulated. Our recent data suggest that loss of STAT3 causes a cascade of events that affect dendritic cell (DC) differentiation, abnormal generation of inflammatory cytokines, polarized Th1 activation, B cell over-proliferation and eventually lead to autoimmune disorders similar to systemic lupus erythematosus (SLE). In particular, we have recently shown that STAT3 activation is a crucial checkpoint of Flt3L-regulated DC development (Immunity, 19, 903, 2003 ). Loss of STAT3 during hematopoiesis resulted in essential elimination of DC population. Surprisingly, DC-elimination in the mice did not cause immunodeficiency, but lead to auto-immune diseases in these mice, suggesting the indispensable function of DC is regulation of immune tolerance. With the unique animal models generated in my lab, we will further investigate molecular mechanisms controlling DC differentiation and search for STAT3 regulated genes that mediate immune tolerance. The role of STAT3 during DC-stimulated T cell differentiation into T helper and regulatory cells will be examined. We will then investigate whether there is a negative feedback loop that controls immune tolerance and cytokine production. These studies will further reveal molecular mechanisms by which STAT3 in control of immune tolerance. I hope that this work will provide a cellular and molecular basis for etiopathology of autoimmune-associated disorders, such as SLE.

Publications
Chin, E. Y., Kitagawa, M., Su, W. S., You, Z.-H., Iwamoto, Y., and Fu, X-.Y. (1996) Cell Growth Arrest and Induction of Cyclin Dependent Kinase Inhibitor p21WAF1/CIP1 Mediated by STAT1. Science 272 : 719-722.

Su, W.-C. S., Kitagawa, M., Xue, N., Xie, B., Garofalo, S., Cho, J., Deng, C., Horton, W. A., and Fu, X.-Y. (1997). STAT1 Activation Induced by Mutant FGFR3 in Thanatophoric Dysplasia Type II. Nature 386, 288-292.

Welte, T., Leitenberg, D, Dittel, B. N. al-Ramadi, B. K., Xie. B., Chin, Y. E., Janeway, Jr., C. A., Alfred L. M. Bothwell, Bottomly, K. and Fu, X.-Y. (1999) STAT5 Interaction with the T-Cell Receptor Complex and Stimulation of T-Cell Proliferation. Science , 283, 222-225

Welte, T., Zhang, S. S., Wang, T., Zhang, Z Yin, Zhinan, Kano, A., Hesslein, D., Iwamoto, Y., Panelakis, K., Bothwell, A. M., Craft, J. E., Fikrig, E., Flavell, E. A., Fu, X.-Y. (2003)   STAT3 Deletion During Hematopoiesis Causes Crohn's Disease-Like Pathogenesis and Lethality, Revealing a Role of STAT3 in Regulation of Innate Immunity. Proc. Natl. Acad. Sci. USA 100 .1879-1884.

Kano, A., Wolfgang, M., Gao, Q., Zhang, S. S-M. Iwamoto, Y., Pober, J., Flavell, R. A. and Fu, X.-Y . (2003) Endothelial cells require STAT3 for protection against endotoxin-induced inflamma tion. Journal of Experimental Medicine, 198, 1517-1525.

Search Pub Med

Return to Homepage