- Microbiology and Immunology
- UNC-Chapel Hill
- 103 Mason Farm Road, 7341C MBRB
Area of Interest
My laboratory is interested in the link between inflammation and cancer. This association is exemplified by the human inflammatory bowel diseases (IBD), the clinical interest of my group. In patients with Crohns (CD) or ulcerative colitis (UC), an annual colorectal cancer rate of 0.5% per year after a decade of inflammatory disease has been described. This risk is increased at least twenty-fold over that of age and sex matched control populations without colitis.
Interactions between the immune system and the environment lead to the initiation and perpetuation of inflammation in IBD. The environmental factor that has attracted the most attention in the pathogenesis of IBD is the enteric microbial flora. We wish to determine at the molecular level how bacteria activate innate immune responses. The major interest of the laboratory is defining the regulated expression of IL-12 family members in macrophages and dendritic cells. A prominent role for the IL-12 family members, IL-12 and IL-23, has been established in the pathogenesis of intracellular infections, chronic inflammation, and cancer. Our laboratory has extensively characterized regulation of the IL-12 p40 promoter. We have identified C/EBP, AP-1, NFAT, and IRF DNA binding elements that are critical for activation of gene expression by bacteria and cytokines. Recently, we have characterized inhibitory pathways for macrophage activation and IL-12 p40 expression. We have described an important inhibitory role for the PI3K pathway in macrophage activation using a novel transgenic mouse mutant for the PI3K p110δ subunit that overexpresses IL-12 p40 and develops IBD.
We are also interested in a second environmental factor that influences the course of IBD. Epidemiologic studies from numerous geographic populations demonstrate that cigarette smoking is protective against the development of UC. We have been studying the potent anti-inflammatory effects of a component of cigarette smoke, carbon monoxide (CO), in mouse models of IBD. Low level CO exposure in IL-10 deficient mice ameliorated chronic intestinal inflammation through a novel pathway that involves upregulation of the enzyme heme oxygenase-1 (HO-1). Further work focuses on molecular mechanisms through which CO and HO-1 exert anti-inflammatory effects.
We also have applied inflammation research to better understand cancer biology. We are currently studying the effects of a novel anti-neoplastic agent, a uroguanylin analog, in the amelioration of inflammation and prevention of colitis-associated dysplasia in IBD mouse models. Most significantly, in collaboration with investigators at the University of Pittsburgh, we have recently reported a novel mouse model of colitis-associated colon cancer. IL-10 deficient mice crossed to human MUC1 transgenic mice develop chronic intestinal inflammation at an earlier age than IL-10 deficient mice and have a higher incidence of colon cancer and increased tumor numbers compared to IL-10 deficient mice.
Awards and Honors
American Society for Clinical Investigation
Director, UNC School of Medicine Federation of Clinical immunology Societies Center of Excellence
UNC Center for Gastrointestinal Biology and Disease Executive Committee (P30 DK34987)
Charter Member-NIDDK Gastrointestinal Biology and Pathobiology Study Section
American Gastroenterological Society Foundation for Digestive Health and Nutrition Grants Review Committee