PEOPLE

Youhai H. Chen, MD, PhD

Professor of Pathology and Laboratory Medicine
University of Pennsylvania Perelman School of Medicine

Contact InformationUniversity 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

Email: yhc@mail.med.upenn.edu

Specialty Division

Immunobiology and Experimental Pathology

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, dereksp@mail.med.upenn.edu
HONGHONG SUN, Senior Research Investigator, hsun2@mail.med.upenn.edu
MARLA KNOB, Administrative Assistant, marla2@mail.med.upenn.edu
SVETLANA FAYNGERT, Senior Research Investigator, sfayn@mail.med.upenn.edu
THOMAS PORTURAS, Ph.D Student, pothomas@mail.med.upenn.edu
GEORGE LUO, Ph.D Student, luog@sas.upenn.edu
Yunwei Lou, Ph.D Student, louyunwei2012@gmail.com
Terry Cathopoulis, Post-Doctoral Researcher, terca@mail.med.upenn.edu
Songli Shi, Visiting Scholar, shisonglin2014@gmail.com
George Buchlis, Post-Doctoral Researcher, buchlis@mail.med.upenn.edu
SAMANTHA MORRISSEY, Lab manager, morrs@sas.upenn.edu
Matthews Lan, Student, mattlan@sas.upenn.edu

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.

Graduate Groups

Cell and Molecular Biology
Immunology

Education

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

Specialty Certification

Postgraduate Training

Resident/Teaching Assistant, Department of Medicine, Shandong University, Shandong, China, 1986-1987
Medical Research Council (MRC) Fellow, Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, 1990-1993
Research Fellow, Center for Neurological Diseases, Brigham and Women's Hospital, Harvard University, Boston, MA, 1993-1995

Awards and Honors

Medical Research Council (MRC) Fellowship Award, 1990-1993
Travel Award, Canadian Society for Immunology, 1992
Medical Research Council (MRC) Scholar Award, 1994-1995
M.A. hon., Arts, University of Pennsylvania, Philadelphia, PA, 2001
Lady Barbara Colyton Prize for Autoimmune Research, 2002
Member, Henry Kunkel Society, 2008

Memberships and Professional Organizations

Canadian Society for Immunology, 1992 - 1995
American Association for the Advancement of Science, 1994 - Present
New York Academy of Science, 1994 - Present
American Society for Gene Therapy, 1995 - Present
American Association of Immunologists, 1995 - Present
Cystic Fibrosis Foundation, 1996 - 1997
Center for Scientific Reviews, National Institutes of Health, 1999 - 2000
Center for Scientific Reviews, National Institutes of Health, 1999 - 2000
Center for Scientific Reviews, National Institutes of Health, 2000 - 2001
Center for Scientific Reviews, National Institutes of Health, 2001 - 2005
Shandong University Alumni Association, 2003 - 2011
Austrian Science Fund, Austria, 2004 - 2007
Center for Scientific Reviews, National Institutes of Health, 2004 - 2005
Michigan Diabetes Research Center, 2004 - 2005
Shandong University Alumni Association, 2005 - 2014
Shandong Eye Institute, China, 2005 - Present
NINDS, National Institutes of Health, 2005 - 2006
NIAID, National Institutes of Health, 2005 - 2006
The Italian Association for Cancer Research, 2006 - 2010
NIAID, National Institutes of Health, 2006 - 2007
Center for Scientific Reviews, National Institutes of Health, 2006 - 2007
Amgen, Inc., 2006 - 2007
Easton Associates, LLC, New York, 2006 - 2007
NIAID, National Institutes of Health, 2007 - 2008
Health Research Board, Ireland, 2007 - 2008
Center for Scientific Reviews, National Institutes of Health, 2007 - 2008
NINDS, National Institutes of Health, 2007 - 2007
L.E.K. Consulting, 2007 - 2009
Cancer Research UK, UK, 2008 - 2009
National Multiple Sclerosis Society, 2008 - 2008
Chinese Academy of Sciences, 2008 - 2009
Ministry of Science and Technology, China, 2009 - 2015
National Multiple Sclerosis Society, 2009 - 2014
Center for Scientific Review, NIH, 2009 - 2009
Center for Scientific Review, NIH, 2009 - 2009
Center for Scientific Review, NIH, 2010 - 2010
Natural Science Foundation of China (NSFC), 2010 - Present
The National Institute of Dental and Craniofacial Research (NIDCR), NIH, 2010 - 2010
National Multiple Sclerosis Society, 2012 - 2015
Center for Scientific Review, National Institutes of Health, 2013 - 2013
Department of Defense, USA, 2013 - 2013
Helmsley Charitable Trust , USA, 2014 - 2014
Center for Scientific Review, National Institutes of Health, 2014 - 2014
Amshenn Inc., 2015 - Present
Binde Inc, 2015 - Present
Center for Scientific Review, National Institutes of Health, 2016 - 2017

Web Links


Selected Publications

Negative regulation of Toll-like receptor signaling by NF-kB p50 ubiquitination blockade.

Carmody, R. J., Q. Ruan, S. Palmer, B. Hilliard, Y. H. Chen, Science 317(5838): 675-678, 2007

TIPE2, a negative regulator of innate and adaptive immunity that maintains immune homeostasis.

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, Cell 133(): 415-426, 2008, PMID:18455983

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Development Of Foxp3+ Regulatory T Cells Is Driven By The c-Rel Enhanceosome

Ruan, Q., V. Kameswaran, Y. Tone, L. Li, H-C. Liou, M.I. Greene, M. Tone, Y.H. Chen, Immunity 31(): 932-940, 2009

Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21

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, Nature Immunology 11(): 141-147, 2010

Transcriptional regulation of the Th17 immune response by IKK(alpha).

Li Li, Ruan Qingguo, Hilliard Brendan, Devirgiliis Jennifer, Karin Michael, Chen Youhai H, The Journal of Experimental Medicine 208(4): 787-96, 2011, PMID:21402739

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The microRNA-21-PDCD4 axis prevents type 1 diabetes by blocking pancreatic beta cell death.

Ruan Qingguo, Wang Ting, Kameswaran Vasumathi, Wei Qin, Johnson Derek S, Matschinsky Franz, Shi Weiyun, Chen Youhai H, Proceedings of the National Academy of Sciences USA 108(29): 12030-12035, 2011, PMID:21730150

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The Th17 immune response is controlled by the Rel-ROR{gamma}-ROR{gamma}T transcriptional axis.

Ruan Qingguo, Kameswaran Vasumathi, Zhang Yan, Zheng Shijun, Sun Jing, Wang Junmei, Devirgiliis Jennifer, Liou Hsiou-Chi, Beg Amer A, Chen Youhai H, The Journal of Experimental Medicine 208(): 2321-33, 2011

The Anti-inflammatory TIPE2 Is an Inhibitor of the Oncogenic Ras.

Gus-Brautbar Yael, Johnson Derek, Zhang Li, Sun Honghong, Wang Peng, Zhang Shirley, Zhang Lining, Chen Youhai H, Molecular Cell 9(45): 610-8, 2012, PMID:22326055

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TIPE3 is the transfer protein of lipid second messengers that promote cancer.

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, Cancer Cell 26(4): 465-78, 2014, PMID:25242044

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