Description of Research Expertise

Research Interests
Autoimmunity, Apoptosis, and Immune Tolerance.

Key words: Gene therapy, genomics, autoimmune diseases, immunologic tolerance, deletion, apoptosis, and therapeutics.

Research Summary
Research Techniques: Molecular and Cellular Biology; Immunology; Genomics; Therapeutics.

Research in Dr. Chen’s laboratory focuses on three major themes: autoimmunity, apoptosis and gene therapy.

1. 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?

2. 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.

3. 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.

Rotation Projects for 2006-2007
1. To determine the roles of NF-kB, TRAIL, Bim and INF-20 in the development, activation, migration and effector function of T cells recognizing self-antigens.
2. To determine the roles of NF-kB, TRAIL, Bim and INF-20 in the death of lymphoid cells, myeloid cells, oligodendrocytes and pancreatic beta cells.
3. To characterize PDCD4/DUG-/- mice.
4. To define the NF-kB network in T cells using functional genomic tools such as ChIP-on-chip and ChIP-SAGE.

Lab personnel:
Carmody, Ruaidhri - Senior Research Investigator
Chen, Youhai - Assoc. Professor
Gong, Shunyou - Post Doc Res
Hilliard, Brendan - Res. Asst. Professor
Hilliard, Anja - Senior Research Investigator
Hudson, Brian - Ph.D. Student
Li, Li - Post Doc Res
Ludwinski, Maciej - Ph.D. Student
Marinelli, Jennifer - Admin. Assistant
Mazaleuskaya, Luda - Student
Palmer, Scott - Ph.D. Student
Raun, Qingguo - Post Doc Res
Sun, HongHong - Senior Research Investigator
Sun, Jing - Res. Specialist
Wan, Xiaochun - Post Doc Res