Inflammatory bowel disease (IBD) is a debilitating intestinal condition with a high physical, psychological and social burden on patients as well as a high economic burden on the health care system as a whole. Although the exact etiology of IBD is unknown, it appears to be mediated by critical interactions between the environment and host genetic factors. Intestinal immune homeostasis (i.e., the return to relative quiescence after a stress) is a critical determinant in preventing the development of chronic disorders.
One of the major challenges in the field is determining how the signals elicited by normal microbial flora are regulated and processed to prevent continuous chronic inflammation while still maintaining the ability to respond to pathogens. In order to maintain equilibrium with this environment, the intestinal immune system consists of multiple tiers each requiring its own maintenance. In the absence of these regulatory mechanisms, tonic signals from microflora to innate immune cells cause systemic inflammation when dysregulated; thus, understanding these molecular safeguards is of critical importance.
My lab seeks to identify genes that contribute to intestinal immune homeostasis and determine how they contribute to the development of intestinal pathologies such as IBD. To achieve this goal, we conducted a forward genetic screen to find genes that are essential to returning balance to the intestinal system. This screen identified numerous genes, many of which are from inflammation, growth factor signaling, and intestinal stem cell proliferation pathways; genes in unexpected pathways (e.g., vesicle trafficking and metabolism) have also been identified. Using CRISPR/Cas9 targeting, we have validated 17 genes that have previously not been described in intestinal homeostasis.
The goals of my laboratory are as following:
- To unbiasedly uncover genes essential for maintaining intestinal homeostasis using a forward genetic screen of ENU mutants and validate them using CRISPR/Cas9
- To examine the role of immune signaling pathways in colitis with an emphasis on macrophage and dendritic cell biology
- To examine the necessary machinery by which the intestinal epithelium is maintained during stress and infection