DESCRIPTION (provided by applicant): Gene copy number (GCN) variation is a newly described phenomenon, which likely contributes significant phenotypic variability within populations. Substantial GCN variation is present in genes that encode defensins, cationic antimicrobial peptides that play an important role in innate immunity to infectious diseases. The gene encoding -defensin 2, which is a key part the innate immune response in skin and mucosal surfaces, varies from 2-12 copies per diploid genome. Recent evidence has linked variation in the BD2 GCN with susceptibility to idiopathic diseases: low GCN increases the risk for Crohn's disease of the colon, while high GCN is associated with increased risk of psoriasis. We recently used the rhesus macaque model to demonstrate that, like in humans, BD2 expression is induced by Helicobacter pylori, a common gastric pathogen that is the causative agent of peptic ulcer and increases the risk for gastric cancer. Furthermore, our preliminary data suggest that rhesus macaques, like humans, have marked variation in BD2 GCN. We hypothesize that variation in BD2 GCN is reflected in expression levels of BD2, and that these differences will affect the outcome of infection with H. pylori. In Aim 1 we will characterize GCN and allelic diversity in the BD2 gene of macaques, and examine the relationship between GCN and expression of BD2 in primary cell culture. In Aim 2 we will identify three groups of macaques with low, intermediate, or high BD2 GNC, and compare their gastric biota and response to experimental challenge with H. pylori. Since only about 5 to 10% of humans infected with H. pylori will have clinical sequelae, while the remainder will have only asymptomatic gastritis, there is considerable interest in understanding host factors that are associated with disease. Understanding the functional relationship between genetic variations in the BD2 gene and H. pylori infection will therefore not only expand our knowledge of the relationship between the innate immune response and infection, but may also provide a translational link to better understand who may benefit from treatment of H. pylori in order to prevent peptic ulcer and gastric cancer. PUBLIC HEALTH RELEVANCE: ?-defensin2 (BD2) is an important innate immune effectors at epithelial surfaces that shows variability in gene copy number (GCN) and is induced by infection with Helicobacter pylori, an important gastric pathogen. We hypothesize that differences in BD2 GCN affect the host inflammatory response, and thus the propensity to develop disease after infection with H. pylori.
|Effective start/end date||6/14/10 → 5/31/12|
- National Institutes of Health: $500,000.00
- Immunology and Microbiology(all)