Wilson Lab Research

The Wilson Lab has reported that H. pylori induces the enzyme spermine oxidase (SMOX), originally known as polyamine oxidase 1, which utilizes the polyamine spermine as substrate. Generation of H2O2 by SMOX 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, NOS2) and hence NO production that is needed for the killing of H. pylori. Upregulation of 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 have shown that induction of the transcription factor MYC by H. pylori enhances ODC transcription and has a causal role in macrophage apoptosis.

We utilize 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 SMOX-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 SMOX and oxidative DNA damage both in vitro and in vivo in a gerbil model. Furthermore, inhibition of ODC or SMOX reduces gastric cancer in the gerbil model. 

These studies led to a clinical trial in Latin America in patients with precancerous gastric lesions, using the polyamine synthesis inhibitor, difluoromethylornithine.

We are also pursuing studies on immune dysregulation and epithelial function 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 and L-arginine availability is compromised in the colon.

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.

The Wilson Lab has reported that the polyamine spermidine is protective in mouse models of colitis. This may be through effects on the gut microbiome and suppression of pro0inflammatory alpha defensins. But, importantly, spermidine is the substrate for the enzyme deoxyhypusine synthase, which generates the amino acid hypusine on eukaryotic translation initiation factor 5A (EIF5A).  

Hypusination of EIF5A enhances protein translation of specific mRNAs, and we have shown that hypusination in intestinal epithelial cells protects against gut inflammation and colorectal carcinogenesis.

Pending grant applications

In addition to the currently funded studies listed on the Wilson Lab home page, we have three pending grant applications:

  • Role of hypusination and NRF2 in colitis and associated colorectal carcinogenesis
  • Role of EIF5A in colorectal cancer
  • Use of inhibitors of the reverse transsuluration pathway as a novel treatment for H. pylori infection.

The Wilson Lab was recently awarded a patent application for the use of electrophile scavengers in gastrointestinal cancers.