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Keith T. Wilson, M.D.

  • Thomas F. Frist, Sr. Professor of Medicine
  • Professor of Medicine (Gastroenterology, Hepatology & Nutrition)
  • Professor of Pathology, Microbiology and Immunology
  • Director of Research, Division of Gastroenterology, Hepatology & Nutrition
  • Director, Vanderbilt Center for Mucosal Inflammation and Cancer

Phone

615-343-5675

Email

keith.wilson@Vanderbilt.Edu
Vanderbilt University Medical Center
1030C MRBIV
Nashville , TN 37232-0252

Keith T. Wilson, M.D.

  • Thomas F. Frist, Sr. Professor of Medicine
  • Professor of Medicine (Gastroenterology, Hepatology & Nutrition)
  • Professor of Pathology, Microbiology and Immunology
  • Director of Research, Division of Gastroenterology, Hepatology & Nutrition
  • Director, Vanderbilt Center for Mucosal Inflammation and Cancer

615-343-5675

keith.wilson@Vanderbilt.Edu

Vanderbilt University Medical Center
1030C MRBIV
Nashville , TN 37232-0252

Profile

An emerging concept over the last decade is that most gastrointestinal malignancies actually arise from chronic inflammation. In keeping with this concept I have made a major component of my research program how the dysregulation of mucosal immune responses can lead to neoplastic transformation.

Exploding knowledge about Helicobacter pylori in the 1990's and the elegance of this area of investigation as a perfect model to study mucosal immunology caused me to study this area for the last 10 years. My work has focused on host response to the infection. These studies have involved the innate immune response and the identification of ways that this response is ineffective. In this context we have also elucidated several important mechanisms whereby the epithelial responses may also be inappropriate, leading to risk for cancer development. My laboratory seeks to unravel novel mechanisms for inflammation and cellular damage, which in the case of H. pylori infection leads to increased cancer risk. One such pathway that we have reported is that H. pylori specifically induces the enzyme spermine oxidase (SMO), originally known as polyamine oxidase 1, which selectively utilizes the polyamine spermine as substrate. Our studies showed that the generation of H2O2 by SMO results in mitochondrial membrane depolarization, cytochrome c release, caspase-3 activation, and apoptosis. Our work has also shown that spermine itself contributes to the inadequacy of the host response, by blocking iNOS translation and hence NO production that is needed for the killing of H. pylori. We have specifically reported that upregulation of SMO is a major source of oxidative stress in gastric epithelial cells that leads to both apoptosis and DNA damage. Our funded studies are focused on the role of SMO in inflammatory responses and the mechanisms of ODC and SMO gene promoter activation. We are now moving further into the direction of the role of SMO in cancer, since we will be working with carcinogenic strains of H. pylori developed at Vanderbilt and a mouse model of gastric cancer, hypergastrinemic INS-GAS mice.

My lab will also be investigating the role of SMO in colon cancer derived from inflammatory bowel disease and in esophageal cancer derived from Barrett's esophagus. We also have substantial experience working with COX-2 in inflammation-associated carcinogenesis in the case of Barrett's esophagus and H. pylori infection.

Education

  • M.D. Harvard Medical School, Boston, Massachusetts (1986)
  • B.A. Cornell University, Ithaca, New York (1982)

Postgraduate Training

  • Residency, Internal Medicine, Case Western Reserve University Hospitals of Cleveland 1986-1989
  • Fellowship, Gastroenterology, University of Chicago, 1989-1993

Research Emphasis

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)

Publications

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