Processing of EGF Ligands in Gut Biology and Cancer

超出所提供的空间。 胃肠道的上皮衬里在宿主和外部环境之间形成连续的保护屏障。因此，这层肠上皮细胞不断暴露于肠腔中存在的有害物质，如细菌及其副产物。在损伤时，先天免疫应答被设计为保护和修复上皮衬里的完整性。作为这种反应的一部分，上皮细胞通过细胞扩散、迁移、增殖和存活对修复屏障功能作出反应。此外，上皮细胞产生趋化因子和角化受体以募集免疫细胞。活化的巨噬细胞释放活性氧和氮物质，并将促炎细胞因子和趋化因子分泌到上皮细胞周围的微环境中。这种先天性免疫应答通常是协调的和自限性的过程，但这些事件的失调导致上皮细胞持续暴露于氧化应激和促炎介质，这可导致慢性炎症、炎性肠病（IBD）和结肠癌发生的风险增加。 通过表皮生长因子受体（EGFR/ErbB 1）的信号传导在肠上皮细胞恢复、增殖和存活中起重要作用，其失调有助于肿瘤进展。炎症刺激和其他生理应激可以激活ErbB信号转导通路，但调节这些信号转导事件的机制知之甚少。最近的研究已经鉴定了TNFa转化酶（ADAM 17/TACE）和其他去整合素-金属蛋白酶（亚当斯）在EGF样生长因子前体的胞外域切割中起重要作用，所述EGF样生长因子前体的胞外域切割导致ErbB反式激活。因此，我们对这项拨款提案的假设是，炎症刺激，如氧化应激和促炎细胞因子可以调节肠上皮细胞中EGF样生长因子和ErbB激活的ADAM依赖性脱落。在慢性炎症期间，这种增强的配体脱落可能导致持续和不适当的ErbB信号传导，这可能有助于IBD的发病机制和结直肠癌的风险。 我研究的长期目标是确定不同EGF样生长因子在肠上皮细胞生物学中的独特生化功能及其对健康和疾病中EGFR信号传导的影响。该资助提案的具体目标是鉴定参与炎症刺激诱导的EGF样配体前体的胞外域脱落的亚当斯，表征调节这些裂解事件的机制，以及检查ADAM 17在肠道内稳态和葡聚糖硫酸钠（DSS）诱导的结肠炎模型中的作用。太平洋西北研究所720百老汇西雅图，WA 98122关键人员=

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===========================================