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Member Information
Youhai H. Chen, M.D., Ph.D.
Associate Professor of Pathology and Laboratory Medicine
University of Pennsylvania School of Medicine
Office Phone: 215-898-4671
Office Fax: 215-573-6725
Email: yhc@mail.med.upenn.edu
Website(s):
Education: MD, Shandong University ; Ph.D., University of Manitoba
Keywords: Immunology; Inflammation; Apoptosis; Transcription.
Research Interests:
Autoimmunity, Apoptosis, and Gene Therapy.
Summary:
Research in Dr. Chen's laboratory focuses on three major themes: autoimmunity, apoptosis and gene therapy.
I. Genes and Genomics of Autoimmune Inflammation: from Rel to TRAIL.
The major goals of Dr. Chen's research program are to understand the molecular mechanisms of autoimmune diseases (such as multiple sclerosis and type 1 diabetes) and to find a cure for these diseases. Although the etiological factors that trigger these diseases vary, the common pathological outcome of autoimmune diseases is the destruction of self-tissues by activated lymphoid and myeloid cells through a process called autoimmune inflammation . Development of autoimmune inflammation requires coordinated expression of myriad genes that mediate the activation, migration and effector functions of inflammatory cells. These include genes that encode antigen receptors, costimulatory molecules, cytokines, chemokines, and cytotoxic enzymes. To explore the spectrum and global patterns of gene expression during autoimmune inflammation, Dr. Chen's laboratory has recently performed functional genomic studies of autoimmune inflammation in the central nervous system (CNS). Inflammation in the CNS not only induced the expression of many immune-related genes, but also significantly altered the gene expression profile of neural cells. A number of unique clusters of genes were identified which represent putative immune and nervous responses in autoimmune inflammation. Using models of immune tolerance and autoimmunity, Dr. Chen and colleagues are exploring the physiological and pathological roles of the following genes: the Rel/nuclear factor (NF)-kB family, Bim and TRAIL as well as a newly cloned gene called inflammation-20 (INF-20) . The following questions are being examined: 1) What are the roles of these genes in the development, activation, migration and effector function of T cells recognizing self-antigens? 2) What are the roles of these genes in the death of lymphoid cells, myeloid cells, oligodendrocytes and pancreatic beta cells?
II. Apoptosis
To elucidate the molecular mechanisms of cell death, Dr. Chen's laboratory has recently isolated a new gene called DUG or PDCD4. DUG is constitutively expressed at low levels in normal cells but is dramatically upregulated during starvation- or Fas-induced apoptosis. The DUG cDNA encodes a protein of 469 amino acids with two putative nuclear localization signals and multiple phosphorylation sites for protein kinases. It shares sequence homology with eukaryotic translation initiation factor (eIF) 4G and, like eIF4G, is able to bind eIF4A. Mice deficient in DUG have been recently generated by germ line gene targeting. These mice develop spontaneous tumors but are resistant to autoimmune inflammation. Further characterization of these mice should provide insights into the roles of DUG in oncogenesis, inflammation and protein translation. Additionally, Dr. Chen and colleagues are also investigating the molecular basis of TRAIL-induced apoptosis and cell cycle inhibition in normal and tumor cells.
III. Gene therapy
Using apoptosis-inducing genes such as FasL and TRAIL, Dr. Chen and colleagues are exploring the potential of apoptosis-based gene therapy for the treatment of autoimmune diseases. One of the current projects is to determine which molecular pathway(s) is responsible for the therapeutic effect of TRAIL in inflammatory diseases.
Representative Publications:
Liu, J., T. Miwa, B. Hilliard, Y. H. Chen, J.D. Lambris, A. D. Wells, W.-C. Song. The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. Journal of Experimental Medicine 201:567-577, 2005.
Zheng, S., P. Wang, G. Tsabary, Y. H. Chen. Critical roles of TRAIL in hepatic cell death and hepatic inflammation. Journal of Clinical Investigation 113:58-64, 2004.
Lamhamedi-Cherradi, S-E., S. Zheng, K. Maguschak, J. Peschon, Y. Chen. Defective Thymocyte Apoptosis and Accelerated Autoimmune Diseases in TRAIL -/- Mice. Nature Immunology 4(3): 255-260, 2003.
Hilliard, B., N. Mason, L. Xu, J. Sun, S-E. Lamhamedi-Cherradi, H-C Liou, C. Hunter, Y. Chen. Critical Roles of c-Rel in Autoimmune Inflammation and Helper T Cell Differentiation. Journal of Clinical Investigation 110:843-850, 2002.
Song, K., Y. Chen, R. Göke, A. Wilmen, A. Göke, Y. Chen. TRAIL Is an Inhibitor of Autoimmune Inflammation and Cell Cycle Progression. Journal of Experimental Medicine 191:1095-1103, 2000.
Zhang, H., Y. Yang, J. L. Horton, E. B. Samoilova, T. A. Judge, L. A. Turka, J. M. Wilson, Y. Chen. Amelioration of collagen-induced arthritis by Fas-ligand gene transfer. Journal of Clinical Investigation 100(8):1951-1957, 1997.
Chen, Y., V.K. Kuchroo, J-I. Inobe, J.L. Baron , C.A. Janeway, H.L. Weiner. Oral tolerance in myelin basic protein T-cell receptor transgenic mice. Proc. Natl. Acad. Sci. USA 93:388-391, 1996.
Chen, Y., J-I. Inobe, R. Marks, P. Gonnella, V.K. Kuchroo, H.L.Weiner. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 376:177-180, 1995.
Chen, Y., J-I. Inobe, V.K. Kuchroo, D.A. Hafler, H.L. Weiner. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:1237-1240, 1994.
