H. pylori remains a major public health problem, since half of the world's population is infected and the associated gastric cancer is the second leading cause of cancer deaths. We have elucidated mechanisms of immune system failure that result in persistence of the organism and sustained oxidative stress that leads to DNA damage. H. pylori induces ornithine decarboxylase (ODC), the rate limiting enzyme for polyamine synthesis, in macrophages. In both in vitro and in vivo models, ODC-derived spermine synthesis results in 1.) apoptosis;and 2.) inhibition of nitric oxide (NO) synthesis, by inhibition of L-arginine (L-Arg)-dependent inducible nitric oxide (NO) synthase (iNOS) protein translation. Inhibition of ODC with oral administration of a- difluoromethylornithine (DFMO) in mice restores L-Arg uptake, macrophage NO production, and cytokine balance, resulting in reduction in both gastritis and H. pylori colonization. H. pylori also up-regulates the enzyme spermine oxidase (SMO), thus generating H2O2, and acting as a novel mechanism for the generation of oxidative stress-associated DNA damage in gastric epithelial cells. We have also discovered another target of H. pylori, heme oxygenase (HO)-1, known for its anti-inflammatory and anti-oxidant properties. We show that H. pylori blocks NO-induced HO-1 in gastric epithelial cells, and this results in unrestrained chemokine synthesis. We hypothesize that H. pylori infection results in failure of antimicrobial and immunoregulatory NO generation and overproduction of polyamines and H2O2, leading to dysregulation of immune responses and survival of gastric epithelial cells with DNA damage. These events lead to persistence of the bacterium, chronic inflammation, and risk for neoplastic transformation.
Our Specific Aims are as follows. 1.) To determine the mechanism of persistence of H. pylori colonization and gastritis due to ODC. We will compare WT and ODC+/-, myeloid-specific ODC-/-, iNOS-/- mice, and appropriate bone marrow chimeras, each ? DFMO, and assess: A.) gastritis and colonization;B.) immune responses;C.) DNA damage and carcinogenesis by comparing WT and ODC mutant x INS-GAS mice, each ? DFMO. 2.) To determine the role of SMO in H. pylori infection, gastritis, and carcinogenesis. We will use SMO-/- mice and assess: A.) colonization, gastritis, advanced lesions, and effects on iNOS;B.) gastric epithelial cell apoptosis and DNA damage;C.) role in carcinogenesis by comparing WT and SMO-/- INS-GAS mice. 3.) To determine the role of HO-1 as a regulator of H. pylori immunopathogenesis and carcinogenesis in vivo by assessing: A.) modulation of HO-1 by polyamines and NO in ODC, SMO, and iNOS KO mice;B.) in mice with normal versus increased NO production and HO-1 expression treated with a pharmacologic inhibitor of HO-1, or in HO-1-/- and epithelial-specific HO-1-/- mice, effects on colonization, gastritis, immune responses, apoptosis, DNA damage, and carcinogenesis. The studies proposed seek new strategies for amelioration or prevention of H. pylori-induced disease by clarifying targets for intervention in the pathogenic immune response that lead to disease persistence and cancer risk.
Helicobacter pylori is a type of bacteria that infects the stomach of half of the world's human population, which can lead to the development of gastric cancer, the second leading cause of cancer death worldwide. In this project we will utilize in vitro and in vivo model systems to assess novel molecular pathways that are altered by H. pylori leading to host responses that fail to eradicate the pathogen, and cause persistent inflammation and DNA damage. The studies proposed seek to define new strategies for amelioration or prevention of H. pylori-induced disease by clarifying targets for intervention in the pathogenic immune response that lead to disease persistence and cancer risk.
|Singh, Kshipra; Coburn, Lori A; Asim, Mohammad et al. (2018) Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses. Cancer Res 78:4303-4315|
|Scoville, Elizabeth A; Allaman, Margaret M; Brown, Caroline T et al. (2018) Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Metabolomics 14:|
|Sierra, Johanna C; Asim, Mohammad; Verriere, Thomas G et al. (2018) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 67:1247-1260|
|Coburn, Lori A; Singh, Kshipra; Asim, Mohammad et al. (2018) Loss of solute carrier family 7 member 2 exacerbates inflammation-associated colon tumorigenesis. Oncogene :|
|Noto, Jennifer M; Chopra, Abha; Loh, John T et al. (2018) Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments. Gut 67:1793-1804|
|Mera, Robertino M; Bravo, Luis E; Camargo, M Constanza et al. (2018) Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 67:1239-1246|
|Hardbower, Dana M; Asim, Mohammad; Luis, Paula B et al. (2017) Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Proc Natl Acad Sci U S A 114:E751-E760|
|Parang, Bobak; Kaz, Andrew M; Barrett, Caitlyn W et al. (2017) BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Gut 66:852-862|
|Hardbower, D M; Coburn, L A; Asim, M et al. (2017) EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis. Oncogene 36:3807-3819|
|Gobert, Alain P; Wilson, Keith T (2017) Effect of CO2 on Peroxynitrite-Mediated Bacteria Killing: Response to Tsikas et al. Trends Microbiol 25:602-603|
Showing the most recent 10 out of 121 publications