Office Address:
1030C MRB IV (37232), Nashville, TN 372320252

Thomas F. Frist Sr. Chair in Medicine

Education

MD - Harvard Medical School

Clinical Interest

Research Keywords
Mucosal immunology, mechanisms of inflammation, oxidative stress and gastrointestinal carcinogenesis, host-pathogen interactions, inflammatory bowel disease, Helicobacter pylori infection, stomach cancer?
Research Description

My laboratory is focused on gastrointestinal mucosal inflammation and carcinogenesis. We study the host immune response to the gastric pathogen Helicobacter pylori that causes peptic ulcer disease and gastric cancer. This includes the innate immune response in macrophages and the identification of ways that this response is ineffective. We have also elucidated mechanisms whereby epithelial responses are inappropriate, leading to risk for cancer development. We study novel mechanisms for inflammation and cellular/DNA damage, which leads to increased cancer risk. We have reported that H. pylori induces the enzyme spermine oxidase (SMOX), which utilizes the polyamine spermine as substrate. Generation of H2O2 by SMOX results in apoptosis of macrophages due to mitochondrial membrane depolarization. Spermine itself contributes to the inadequacy of the host response, by blocking translation of inducible nitric oxide (NO) synthase (iNOS) and hence NO production that is needed for the killing of H. pylori. SMOX causes oxidative stress in gastric epithelial cells that leads to both apoptosis and DNA damage. Induction of ornithine decarboxylase (ODC) that generates polyamines also leads to apoptosis of macrophages, contributing to loss of host innate immunity to H. pylori. We recently reported that myeloid-specific knockout of Odc leads to increased immune activation and inflammation in the mouse H. pylori infection model. Another recent discovery in our lab was that epidermal growth factor receptor (EGFR) phosphorylation is an important part of the host response to activating stimuli, such as H. pylori or the colitis-inducing bacterium, Citrobacter rodentium, in macrophages. Mice with myeloid-specific deletion of EGFR exhibited decreased H. pylori-induced gastritis, C. rodentium-induced colitis, and less tumors in the AOM-DSS model of colitis-associated carcinogenesis. Further, we also reported that an EGFR inhibitor given in the food markedly attenuated gastric carcinoma development in the mouse INS-GAS and gerbil models of H. pylori-induced cancer. We are extensively utilizing clinical material from cohorts of human subjects from Colombia and Central America, where H. pylori infection prevalence is very high, but gastric cancer risk is much higher in the mountains when compared to the coastal regions. Our studies implicated the polyamine-driven oxidative stress and associated DNA damage. Work showing that an inhibitor of polyamide synthesis reduced gastric inflammation and cancer in rodents led to a clinical trial that we are conducting with this agent (difluoromethylornithine) in human subjects with precancerous gastric lesions. We are also pursuing studies on immune dysregulation in inflammatory bowel disease. This includes work on arginine availability/transport, polyamines, nitric oxide. and the micro biome. We have reported that levels of the amino acid L-arginine are decreased in the tissues of humans with ulcerative colitis. Because L-arginine is important in regulation of epithelial integrity and immune function a defect in the utilization of L-arginine could contribute to the disease pathogenesis. Consistent with this, we have shown that treatment with L-arginine improves colitis in mouse models. Further, mice lacking an inducible L-arginine transporter have increased disease activity in the DSS injury model but reduced colitis in the C. rodentium infection model. We are investigating alterations in the microbiome as a potential contributor to these differences. Our funded studies are focused on: 1) Mechanisms of H. pylori induced immune dysregulation, arginine metabolism in the immune response and disease progression (PI, VA Merit Review Grant) 2) Oxidative stress and EGFR activation in the development of gastric cancer in Colombia, and the importance of H. pylori strains from regions of low and high gastric cancer risk in modulation of host responses (PI, P01 grant) 3) Role of EGFR signaling and polyamines in epithelial dysfunction in H. pylori infection and carcinogenesis (PI, project on second P01) 4) Inhibition of polyamine synthesis with difluoromethylornithine in human subjects in Colombia and Honduras with precancerous gastric lesions (PI, R01 grant). 5) Arginine and other amino acids as immunomodulatory agents and potential therapies in colitis and colitis-associated cancer (PI, R01 grant)