Microbiology and Immunology
Area of interest
My laboratory has been studying development and function of the human immune system, as well as HIV-1 infection and immuno-pathogenesis, in various in vivo models. We are also developing new humanized mouse models to study immuno-pathogenesis of chronic HBV and HCV infection in vivo. In addition, we are investigating human stem cell biology (ES cells, HSC and human liver progenitor cells) in humanized mouse models.
1. Novel humanized mouse models to study human HSC and liver progenitor cells. A functional human immune system is reconstituted in the humanized Rag2-gC double knockout mouse model (DKO-hu HSC mice). In addition, we have used human liver progenitor cells to reconstitute DKO mice with human liver cells (DKO-hu HSC/Liv mice). We are also genetically characterizing human HSC or liver progenitor cells in self-renewal, differentiation and cancer. In addition, we are investigating how to derive HSC or liver progenitor cells from human ES cells.
2. HIV-1 Infection and immuno-pathogenesis in lymphoid organs and in animal models. The human fetal thymic organ culture (HF-TOC) and SCID-hu Thy/Liv mouse models are used to explore the mechanisms of intrathymic T cell development and pathophysiology of HIV-1 infection in human lymphoid organs. We focus on defining viral and host pathogenic factors that are involved in HIV-1 replication and pathogenesis. In addition, we have used the DKO-hu HSC model to study function of the human immune system, and immuno-pathogenesis of HIV-1.
3. Development and function of regulatory T (Treg) cells, and their role in HIV-1 infection and immuno-pathogenesis. Regulatory CD4+CD25+FoxP3+ T cells developed in the thymus are critical to suppress self-reactive T cells in mice and human. We are investigating the molecular mechanisms of Treg development and functions, and of their anergic state in cell cycle progression and cytokine gene expression. We are particularly focusing on the epigenetic mechanisms of expression and function of FoxP3 and the consequence of HIV-1 infection on the function of Treg cells. In addition, we have been investigating the role of Treg cells in HIV-1 infection and pathogenesis in the DKO-hu HSC model in vivo.
4. Modeling immuno-pathogenesis and immuno-therapeutics of chronic HBV/HCV/HIV. Immuno-tolerance and chronic inflammation in the liver are associated with chronic infection of HBV/HCV, and are major contributors of liver diseases including fibrosis/cirrhosis and HCC. HIV-1 coinfection has been correlated with accelerated liver disease progression in HCV/HBV infected patients. The long-term goals are 1) to elucidate immunopathogenic mechanisms of HBV/HCV and the contribution of HIV-1 coinfection and abnormal inflammation; 2) to develop novel therapeutics including anti-HBV/HCV siRNA and immuno-therapeutics; and 3) to develop novel approaches to regenerating human livers that are resistant to HBV/HCV infection with genetically modified human ES and liver progenitor cells.