EXCEED THE SPACE PROVIDED. The epithelial lining of the gastrointestinal tract forms a continuous protective barrier between the host and the external environment. This layer of intestinal epithelial cells is therefore constantly exposed to injurious agents present in the gut lumen such as bacteria and their by-products. Upon injury, the innate immune response is designed to protect and repair the integrity of the epithelial lining. As part of this response, the epithelial cells respond to repair barrier function through cell spreading, migration, proliferation and survival. Additionally, the epithelial cells produce chemokines and horning receptors to recruit immune cells. Activated macrophages release reactive oxygen and nitrogen species and secrete pro-inflammatory cytokines and chemokines into the microenvironment surrounding the epithelial cells. This innate immune response is normally a co-ordinated and self-limiting process but deregulation of these events results in sustained exposure of the epithelial cells to oxidative stress and pro-inflammatory mediators that can lead to chronic inflammation, inflammatory bowel disease (IBD) and increased risk of colon carcinogenesis. Signaling through the epidermal growth factor receptor (EGFR/ErbB1) plays an important role in intestinal epithelial cell restitution, proliferation and survival, and its deregulation contributes to neoplastic progression. It is well recognized that inflammatory stimuli and other physiological stresses can activate ErbB signal transduction pathways but the mechanisms regulating these signaling events are poorly understood. Recent studies have identified TNFcc converting enzyme (ADAM17/TACE) and other disintegrin- metalloproteases (ADAMs) as playing an essential role in the ectodomain cleavage of EGF-like growth factor precursors that leads to ErbB transactivation. Therefore, our hypothesis for this grant proposal is that inflammatory stimuli such as oxidative stress and pro-inflammatory cytokines can modulate ADAM- dependent shedding of EGF-like growth factors and ErbB activation in intestinal epithelial cells. During chronic inflammation, this enhanced ligand shedding could cause persistent and inappropriate ErbB signaling that may contribute to the pathogenesis of IBD and risk of colorectal cancer. The long-term objectives of my research are to determine the unique biochemical functions of the different EGF-like growth factors in intestinal epithelial cell biology and their implications for EGFR signaling in health and disease. The specific goals of this grant proposal are to identify the ADAMs involved in the ectodomain shedding of EGF-like ligand precursors induced by inflammatory stimuli, to characterize the mechanism(s) that regulate these cleavage events as well as to examine the role of ADAM17 in intestinal homeostasis and in the dextran sodium sulfate (DSS)-induced colitis model in vivo. Pacific Northwest Research Institute 720 Broadway Seattle, WA 98122 KEY PERSONNEL ========================================Section End===========================================
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