In a healthy human adult the single layer of intestinal epithelial cells (IEC) lining the gastro-intestinal tract replenishes itself approx. every 4-5 days. This high rate of proliferation is second only to haemopoetic cell lineages, therefore IEC represent a population of cells requiring careful regulation of cell division. Recent studies have highlighted the role of microbial-sensing Toll-like receptors (TLR) in maintaining IEC homeostasis. Under some circumstances, such as following insult to the intestine during pathogenic viral and helminth infection, hyper-proliferation of the epithelium is required to expel the invading pathogen. However, sustained excessive proliferation of IEC can lead to dysplasia and cancer. Identifying factors that govern the balance between intestinal replenishment and resistance to infection, without predisposing to dysplasia and cancer, is key to understanding how intestinal homeostasis is maintained. Evidence implicates suppressor of cytokine signalling 3 (SOCS3) as a modulator of cellular proliferation. SOCS3 acts as a negative feedback inhibitor to regulate TLR-induced inflammatory signalling pathways that promote proliferation. In 2007, the P.I. published studies showing that SOCS3 inhibited growth of colonic tumours in a model of inflammation-induced cancer. The experiments outlined in this proposal are designed to investigate the role of SOCS3 in balancing the magnitude and/or duration of "inflammatory" signalling, controlling normal IEC homeostasis, using both in vitro and in vivo models. Understanding the mechanisms that control IEC homeostasis are key to future therapies to modulate the rate of epithelial replenishment, repair and renewal important in many diseases such as intestinal pathogen infection, inflammatory bowel disease and colon cancer.