Intestinal Epithelial Cells
A fundamental function of the intestinal epithelium is to regulate the bidirectional flux of molecules across its barrier, and the lack of proper barrier regulation is central to human pathologic entities such as inflammatory bowel disease and enteric infection. The integrity of this barrier is determined primarily by the apical junction complex (AJC)—a multiprotein organelle comprised of the tight junction (TJ) and adherens junction (AJ), which is intimately linked to the intracellular actin cytoskeleton, and forms an occlusive seam between neighboring epithelial cells. The AJC is highly dynamic, and maintenance of this barrier requires the ability to rapidly adjust levels of junction proteins such as JAM, occludin, claudins, and ZO-1. Rapid control of junction protein composition cannot be regulated at the level of transcription alone, and junction proteins must therefore exist in preformed cytoplasmic or membrane-bound pools, ready for rapid mobilization into or out of the AJC. Despite the critical importance of the AJC as a determinant of epithelial function, relatively little is known about the fundamental mechanisms that control the transport of junction proteins to and from the AJC. Our lab is actively investigating the cellular constituents and mechanisms that function in AJC assembly and turnover.
Immune Cells and Cytokines
Over the past two decades, numerous mouse models of inflammatory bowel disease (IBD) demonstrate a critical role for balancing T cell responses to maintain intestinal immune homeostasis. In addition to T cells, recent data indicate that innate immune cells known as dendritic cells are sufficient to trigger colitis if they have functional defects even in the absence of adaptive immune T cells. Moreover, primary immune deficiencies, which can affect both the innate and adaptive immune systems, are frequently associated with intestinal inflammation. However, because of the broad distribution of immune cells affected by immunodeficiencies, the precise roles of the adaptive and innate immune cells during initiation of an inflammatory response remain unclear. Our research aims to dissect the molecular mechanisms by which innate immune cells instruct adaptive immune T cells to become regulatory T cells with anti-inflammatory functions or effector T cells that drive gut inflammation.
The regulation of cytokines (proteins secreted by immune and epithelial cells) in the intestine and lymphoid organs is critical for the overall digestive health. The involvement of cytokines, particularly pro-inflammatory cytokines like TNF, are commonly elevated in patients with IBD and associated with disease pathogenesis. Current therapeutic strategies have focused on blocking pro-inflammatory cytokines and though effective, are not without complications and side effects. On the other hand, IL-10 is a cytokinethat has been shown to mediate a range of anti-inflammatory activities, and numerous studies have demonstrated its importance in IBD. IL-10-mediated signaling inhibits the induction of pro-inflammatory cytokines. IL-10Rb deficient mice develop spontaneous colitis and our lab was a part of a study that reported that children harboring mutations in the IL-10R genes develop severe early onset IBD. In addition, we recently identified polymorphisms within the IL-10R genes that are associated with increased risk of early onset ulcerative colitis. We are now studying the mechanisms of how IL-10R signaling in different immune cells is involved in maintaining mucosal homeostasis and how defective signaling can lead to perturbations in mucosal homeostasis. Understanding these mechanisms will provide new insights and therapeutic approaches for treating patients with IBD.