Modulation of Host Responses to Microbial Products
Abstract
Inflammatory bowel disease (IBD) is characterized by dysregulated host:microbial interactions and cytokine production. Recognition of and responses to microbes are mediated by host receptors known as pattern recognition receptors (PRRs). When responses through PRRs are either too high or too low, the risk of intestinal inflammation increases, thereby highlighting the importance of the balance in regulation of responses to microbial components in intestinal tissues. Despite the success in identification of IBD-associated genetic regions, the manner in which these genetic associations contribute to IBD is unclear. One such region encompasses the LACC1 gene, which is associated with susceptibility to Crohn s disease. A role for mammalian LACC1 has not yet been described. We have preliminary data demonstrating an important role for LACC1 in reactive oxygen species generation, signaling, cytokines, and bacterial clearance in primary human cells upon exposure with microbial components. The Crohn s disease risk allele in LACC1 results in a change in the LACC1 protein; the isoleucine amino acid at position 254 is changed to a valine. In preliminary data we found that upon exposure to microbial products, cytokines are decreased in cells from individuals who carry this Crohn s disease-associated change in the LACC1 protein. We hypothesize that besides the pathways that we have identified for LACC1 in regulating outcomes to microbial products, there will be a number of additional mechanisms through which LACC1 regulates microbial product outcomes and that these outcomes will be modulated in a LACC1 genotype-dependent manner in human cells. We further hypothesize that these various LACC1-mediated functions will then modulate responses to intestinal pathogens and intestinal inflammation in vivo in mouse models. We will integrate the in vitro findings in primary human cells, which are directly pertinent to human disease, with in vivo mouse studies. The proposed studies will provide novel insight into a gene that confers susceptibility to Crohn s disease, and whose function has been undefined in mammalian systems. This insight will be critical in understanding how LACC1 contributes to Crohn s disease pathogenesis, as well as to ultimately therapeutically targeting LACC1-associated pathways in Crohn s disease patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610178
Entities
People
- Clara Abraham
Organizations
- United States Army
- Yale University