Yi-Guang Chen, PhD
Department of Pediatrics
8701 Watertown Plank Rd
Milwaukee, WI 53226
Phone: (414) 456-7583
Fax: (414) 456-6663
BS, National Taiwan University, Taiwan, 1993
PhD, University of Rochester, 2002
Postdoctoral, The Jackson Laboratory, 2002-2007
The genetic basis of immunological tolerance induction defects in type 1 diabetes
The overall goal of our laboratory is to understand the genetic basis of immunological tolerance induction defects leading to the development of autoimmune diseases with a focus on type 1 diabetes (T1D). In both humans and NOD mice, T1D is a polygenic disease that results from autoimmune mediated destruction of insulin producing pancreatic β-cells. Therefore, further understanding the genetic mechanisms that normally maintain immunological tolerance can be gained by identifying the pathogenic basis of T1D in NOD mice. In these disease susceptible mice, T1D develops as a consequence of an imbalance between immune regulatory and effector T cell subsets, which in turn is controlled by a large number of susceptibility genes. We have found a region on Chromosome (Chr) 4 in NOD mice impairs the development and/or function of two types of immunoregulatory cell population, Foxp3+ regulatory T cells (Tregs) and CD1d-restricted invariant NKT (iNKT) cells. Our current effort is to identify the underlying genes that are responsible for regulating these immunoregulatory T cells and how these regulators control T1D development in NOD mice. Recent studies in humans also indicate that dysfunction of Tregs contributes to T1D development. Therefore, understanding the genetic basis of Treg dysfunction in NOD mice will have important clinical implications. The functional and numerical defects of iNKT cells clearly contribute to T1D development in NOD mice. However, the role of iNKT cells in human T1D is controversial. To further address this question, we will determine if genes can be identified that control both T1D development and iNKT cells. More than 40 T1D loci have been identified by genome wide association studies in humans. We will use mouse genetics approaches to identify loci in addition to the one on Chr4 that regulate the development and function of iNKT cells and ask if the human syntenic regions also modulate T1D development. We will survey a large panel of mouse inbred strains and use genome wide association mapping and quantitative trait locus analysis to identify chromosomal regions important for iNKT cell development and function. We are also developing methods that can treat T1D in NOD mice. While a large number of treatments have been shown to prevent T1D in NOD mice, it has been a challenge to reverse the disease after its onset. We will further improve the efficacy of previously developed methods or design new treatments for T1D reversal in NOD mice with the hope that some of these can be translated into clinic. One of such treatments is the administration of the iNKT cell agonist α-galactosylceramide (GalCer). While this compound prevents T1D when administered to young NOD mice, it can not reverse the disease. We will explore other means of GalCer delivery and iNKT cell based methods to improve the therapeutic efficacy.
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