VICC toll-free number
1-877-936-8422

The VICC.ORG Investigator Directory

Keith T. Wilson, M.D.

Professor of Medicine (Gastroenterology, Hepatology, & Nutrition)
Professor of Cancer Biology
Director of Research and Director of Fellowship Training Program, Division of Gastroenterology, Hepatology, & Nutrition
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
1030C MRBIV
Nashville , TN 37232-0252
615-343-5675
Fax: 615-343-6229

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.

Research Specialty:

Mucosal immunology, mechanisms of inflammation, oxidative stress and gastrointestinal carcinogenesis, host-pathogen interactions

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 (SMO), originally known as polyamine oxidase 1, which utilizes the polyamine spermine as substrate. Generation of H2O2 by SMO results in mitochondrial membrane depolarization, cytochrome c release, and apoptosis. 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. Upregulation of SMO 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 have shown that induction of the transcription factor c-Myc by H. pylori enhances ODC transcription and has a causal role in macrophage apoptosis. We have also implicated formation of a specific AP-1 complex in the activation of c-Myc.

We are utilizing clinical material from a large cohort of human subjects from Colombia, South America where H. pylori infection prevalence is very high, but gastric cancer risk is 25-fold higher in the Andean mountains when compared to the coastal region. We have found that SMO-dependent oxidative stress is increased in gastric epithelial cells in vivo in the subjects at high risk for gastric cancer and that H. pylori clinical strains from these subjects induce more SMO and oxidative DNA damage both in vitro and in vivo in a gerbil model. Studies are ongoing to pursue the mechanisms involved in the differential induction of SMO and DNA damage.

We are also pursuing studies on immune dysregulation in inflammatory bowel disease. This includes work on arginine availability/transport, polyamines, and nitric oxide. We have reported that levels of the amino acid L-arginine are increased in the serum 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 and that mice lacking an inducible L-arginine transporter have increased disease activity.

Our funded studies are focused on:

1) Mechanisms of H. pylori induced DNA damage and immune dysregulation, with an emphasis on the effects of polyamines and their oxidation (PI, R01 grant)

2) The role oxidative and nitrosative stress 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, project on P01)

3) Importance of arginine metabolism in the immune response to H. pylori (PI, VA Merit Review Grant)

4) Role of SMO in EGF signaling and epithelial dysfunction in H. pylori infection (PI, project on P01)

5) Arginine and other amino acids as immunomodulatory agents and potential therapies in colitis and colitis-associated cancer (PI- R01 grant)

6) Prospective clinical study investigating alterations in arginine and other amino acids in ulcerative colitis (PI- R01 supplement; funding completed, analysis ongoing)

Publications:

Education

  • B.A. Cornell University, 1982
  • M.D. Harvard Medical School, 1986
  • Residency, Internal Medicine, Case Western Reserve University Hospitals of Cleveland 1986-1989
  • Fellowship, Gastroenterology, University of Chicago, 1989-1993

You do not have JavaScript enabled. This site works better with JavaScript turned on.