Youhai H. Chen

faculty photo
Professor of Pathology and Laboratory Medicine
Member, Institute for Human Gene Therapy
Member, Cancer Center
Member, Center for Molecular Studies in Digestive and Liver Diseases
Member, Institute of Neurological Science
Member, Penn Center for Musculoskeletal Disorders
Member, Penn Genomics Institute
Member, Institute for Diabetes, Obesity and Metabolism
Member, Clinical Immunology Center
Member, Curriculum Committee, Gene Therapy Graduate Program, CAMB, University of Pennsylvania
Member, Executive Committee, Gene Therapy Graduate Program, CAMB, University of Pennsylvania
Department: Pathology and Laboratory Medicine

Contact information
University of Pennsylvania School of Medicine
Department of Pathology and Laboratory Medicine
713 Stellar-Chance Laboratories
422 Curie Blvd.
Philadelphia, PA 19104
Office: (215) 898-4671
Fax: (215) 573-3434
Graduate Group Affiliations
M.D. (Medicine)
Shandong University, Shandong, China, 1986.
Ph.D. (Immunology)
University of Manitoba, Winnipeg, Manitoba, Canada, 1993.
Post-Doc. (Immunology)
Harvard University, Boston, Massachusetts, USA, 1995.
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Description of Research Expertise

Research Interests
Immunity, Inflammation, Immunotherapy, and Gene Therapy.

Key words: Gene therapy, autoimmune diseases, cancer, immunity, inflammation, Car-T therapy.

Research Summary
Research Techniques: Molecular and Cellular Biology; Immunology; Genomics; Car-T therapy.

I. Genes and Genomics of Autoimmune Inflammation. A major goal of Dr. Chen’s research program is to understand the molecular mechanisms of inflammatory 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 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 inflammation, Dr. Chen and colleagues are exploring the physiological and pathological roles of the following genes: the Rel/nuclear factor (NF)-kB family, microRNA-21, and Pdcd4. The following questions are being examined: 1) What are the roles of these genes in the activation, differentiation, and effector function of inflammatory cells following antigen or Toll-like receptor activation? 2) What are the roles of these genes in the death of lymphoid cells, myeloid cells, oligodendrocytes and pancreatic beta cells?

II. Regulation of Toll-like Receptor Signaling. Toll-like receptors (TLRs) trigger the production of inflammatory cytokines and shape adaptive and innate immunity to pathogens. However, over-activation of TLRs can lead to deleterious inflammatory diseases. Dr. Chen and colleagues have recently found that B cell leukemia (Bcl)-3 plays an essential role in limiting TLR activation. By blocking ubiquitination of NF-κB p50, Bcl-3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl-3-deficient mice and cells are hypersensitive to TLR activation and unable to control responses to lipopolysacchrides. Thus, p50 ubiquitination blockade by Bcl-3 limits the strength of TLR response and maintains innate immune homeostasis. The molecular mechanisms through which p50 ubiquitination is regulated by Bcl-3 are the focus of the current investigation.

III. Inflammation and Cancer. The connection between cancer and inflammation is widely recognized, yet the underlying molecular mechanisms are poorly understood. Dr. Chen and colleagues have recently found that TIPE2 provides a molecular bridge from inflammation to cancer by targeting the Ras signaling pathway. TIPE2 binds the Ras-interacting domain of the RalGDS family of proteins, which are essential effectors of activated Ras. This binding prevented Ras from forming an active complex, thereby inhibiting the activation of the downstream signaling molecules Ral and AKT. Consequently, TIPE2 deficiency led to heightened activation of Ral and AKT, resistance to cell death, increased migration, and dysregulation of exocyst complex formation. Conversely, TIPE2 overexpression induced cell death and significantly inhibited Ras-induced tumorigenesis in mice. Importantly, TIPE2 expression was either completely lost or significantly downregulated in human hepatic cancer. Thus, TIPE2 is an inhibitor of both inflammation and cancer, and a potential drug target for inflammatory and neoplastic diseases. Dr. Chen and colleagues are investigating the molecular mechanisms of TIPE2 action in immunity, inflammation, and cancer.

IV. Immunotherapy and Gene Therapy. Targeting apoptosis-inducing genes such as DR5, Dr. Chen and colleagues are exploring the potential of Car-T and gene therapy approaches for the treatment of cancer and autoimmune diseases.

Potential Rotation Projects:

1. To determine the roles of NF-kB and TIPE proteins in the activation and effector function of inflammatory cells.
2. To determine the roles of NF-kB and TIPE2 in the death of lymphoid cells, myeloid cells, oligodendrocytes and pancreatic beta cells.
3. To characterize the TIPE family signaling pathways.
4. To define the NF-kB network in T cells and myeloid cells using functional genomic tools such as ChIP-on-chip and ChIP-SAGE.

Lab Personnel:

DEREK JOHNSON, Post-Doctoral Researcher,
HONGHONG SUN, Senior Research Investigator,
MARLA KNOB, Administrative Assistant,
SVETLANA FAYNGERT, Senior Research Investigator,
GEORGE LUO, Ph.D Student,
Yunwei Lou, Ph.D Student,
Terry Cathopoulis, Post-Doctoral Researcher,
Songli Shi, Visiting Scholar,
George Buchlis, Post-Doctoral Researcher,
Matthews Lan, Student,

Description of Itmat Expertise

Dr. Chen's research focuses on developing new drugs for treating inflammatory diseases, including current testing of small molecule inhibitors of the nuclear factor kappa B pathway.

Selected Publications

Carmody, R. J., Q. Ruan, S. Palmer, B. Hilliard, Y. H. Chen: Negative regulation of Toll-like receptor signaling by NF-kB p50 ubiquitination blockade. Science 317(5838): 675-678, 2007.

Sun, H., S. Gong, R. J. Carmody, A. Hilliard, L. Li, J. Sun, L. Xu, B. Hilliard, S. Hu, H. Shen, X. Yang, Y. H. Chen: TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis. Cell 133: 415-426, 2008.

Ruan, Q., V. Kameswaran, Y. Tone, L. Li, H-C. Liou, M.I. Greene, M. Tone, Y.H. Chen: Development Of Foxp3+ Regulatory T Cells Is Driven By The c-Rel Enhanceosome. Immunity 31: 932-940, 2009.

Sheedy, F.J., E. Palsson-McDermott, E.J. Hennessy, C. Martin, J. O’Leary, Q. Ruan, D.P Johnson, Y.H. Chen, and L.A.J. O’Neill: Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nature Immunology 11: 141-147, 2010.

Li Li, Ruan Qingguo, Hilliard Brendan, Devirgiliis Jennifer, Karin Michael, Chen Youhai H: Transcriptional regulation of the Th17 immune response by IKK(alpha). The Journal of Experimental Medicine 208(4): 787-96, Apr 2011.

Ruan Qingguo, Wang Ting, Kameswaran Vasumathi, Wei Qin, Johnson Derek S, Matschinsky Franz, Shi Weiyun, Chen Youhai H: The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death. Proceedings of the National Academy of Sciences USA 108(29): 12030-12035, Jul 2011.

Ruan Qingguo, Kameswaran Vasumathi, Zhang Yan, Zheng Shijun, Sun Jing, Wang Junmei, Devirgiliis Jennifer, Liou Hsiou-Chi, Beg Amer A, Chen Youhai H: The Th17 immune response is controlled by the Rel-ROR{gamma}-ROR{gamma}T transcriptional axis. The Journal of Experimental Medicine 208: 2321-33, Oct 2011.

Gus-Brautbar Yael, Johnson Derek, Zhang Li, Sun Honghong, Wang Peng, Zhang Shirley, Zhang Lining, Chen Youhai H: The Anti-inflammatory TIPE2 Is an Inhibitor of the Oncogenic Ras. Molecular Cell 9(45): 610-8, Feb 2012.

Fayngerts Svetlana A, Wu Jianping, Oxley Camilla L, Liu Xianglan, Vourekas Anastassios, Cathopoulis Terry, Wang Zhaojun, Cui Jian, Liu Suxia, Sun Honghong, Lemmon Mark A, Zhang Lining, Shi Yigong, Chen Youhai H: TIPE3 is the transfer protein of lipid second messengers that promote cancer. Cancer Cell 26(4): 465-78, Oct 2014.

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Last updated: 01/01/2017
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