Stress-induced intestinal disorders such as Irritable Bowel Syndrome are the most economically burdensome gastrointestinal diseases known. The long-term objective of the research proposed in my K08 application is to study the basic mechanisms of psychological stress-induced breakdown of intestinal barrier function which is a key underlying event responsible for activation of intestinal disease. In previous animal studies, we demonstrated that enteric corticotrophin releasing factor (CRF) and its receptors play a major role in stress-induced breakdown of intestinal barrier function characterized by increased intestinal permeability. My recent findings revealed an important role of intestinal mast cells (MCs) as key effector cells in this mucosal stress response. We hypothesize that psychological stress stimulates enteric release of CRF that binds to intestinal MCs, via CRF receptors, triggering MC tryptase release and breakdown in intestinal barrier function. We will test this hypothesis in three Specific Aims: 1) Determine if CRF activates MCs via CRF receptors resulting in increased intestinal permeability, 2) Determine if MC tryptase is the key MC mediator triggering increases in intestinal permeability, and 3) Determine if CRF-MC signaling pathways mediate psychological stress-induced barrier dysfunction in vivo.
In Specific Aims 1 and 2, we will utilize in vitro MC-intestinal epithelial coculture systems to study the interactions between CRF and CRF receptors expressed on MCs and how these interactions initiate signaling events that lead to disturbed intestinal epithelial barrier function. We will employ a variety of molecular, genetic, and pharmacological approaches in this model to test my hypothesis.
In Specific Aim 3, we will utilize a mouse model of early life psychological stress to induce permanent disturbances in colonic mucosa barrier function thus mimicking stress-related disease in humans. We will utilize MC-deficient mice combined with molecular-based approaches to determine the definitive role of CRF-MC signaling in psychological stress induced barrier dysfunction.
This research will improve our understanding of the basic mechanisms of CRF-MC signaling and should have important implications in the future design of targeted therapeutic strategies to treat these costly disorders.
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