Our Faculty : Primary Faculty

Zhibin Chen, Ph.D.

Overall, a major goal of our research program is to bridge genetic and genomic discoveries to biology and pathophysiology of human diseases. Specifically, we build animal models to mimic human genetic variations and use the animal models to dissect genetically pre-disposed mechanisms of diseases and possible interventions. The novel gene expression profiles discovered in the animal models are also examined in clinical samples of human diseases for identification of potential novel biomarkers.
This overall strategy is illustrated in our focus on the cytotoxic lymphocyte antigen 4 (CTLA4) gene so far. CTLA4 is a master regulator of the immune system. As an illustration of its critical function in humans, haploinsufficiency can cause type 1 diabetes and stomach cancer in the same patient. The genetic locus for this gene is highly polymorphic. As typical of many other genetic discoveries, most of the genetic variations do not cause qualitative changes of CTLA4 protein, but cause quantitative variations of CTLA4 expression levels and ratios of its various splice variants. We use RNAi transgenic mouse models to model CTLA4 insufficiencies, and then examine how the variations affect development of diabetes or various types of cancer (Figure 1).

Figure 1. Autoimmune and inflammatory mechanisms in diabetes and cancer. A major focus of our studies is based on CTLA4-mediated molecular and cellular pathways of immune regulation. CTLA4 is a critical molecular controller of the immune system. The polymorphisms of the CTLA4 locus cause quantitative variations in CTLA4 expression among human individuals. Those polymorphisms are also associated with genetic risks of diabetes or various types of cancers. We make unique transgenic mouse models to mimic the impact of human CTLA4 genetic variations. We use those animal models to study how CTLA4 regulates diabetes or cancer development in vivo, and to identify potential novel therapies. We also analyze gene-expression network of CTLA4 and other immune genes in different stages of human diabetes, to identify potential biomarkers for possible use in clinical monitoring and management of diabetes.

Dr. Chen’s team has made a number of discoveries. They discovered the intricate relationship between autoimmunity and cancer. They discovered bystander tissue cell growth as a mechanism of tissue regeneration and identified a key role for autoimmune effector memory T cells in causing type 1 diabetes. They discovered cross-differentiation from the CD8 killer T cell lineage to CD4 protective T cells as a “selfless” mode of immune tolerance induction. In collaboration with computational biologists, they discovered a transcriptome signature of human breast cancer impinged by alternative splicing.

Current Research Interests
• Cross-differentiation of T cell lineages, immune memory and immune tolerance.

• Mechanisms of autoimmunity as a double agent in tumor killing and cancer promotion.

• Mechanisms of tissue repairing and regeneration at the site of immune damage

• Epigenetic dysregulation during aging-associated carcinogenesis

• Tumor transcriptome diversification by alternative splicing

Research Profile
Pubmed Link