Inflammatory Bowel disease (IBD) is an incurable disease, for which identification of novel therapeutic targets is a high priority. According to the CDC, there are 1-1.3 million cases of IBD in the United States and the prevalence of this disease is expected to rise in the future. Within the IBD patient population, about half of the patients were diagnosed with Crohn's Disease and the other half diagnosed with Ulcerative Colitis. The current treatments for IBD consist of anti-inflammatory drugs which are both expensive and often ineffective. In order to improve upon our current repertoire of treatments for IBD, we must further our understanding of the biology of the disease by elucidating the specific cellular mechanisms and pathways involved. One of the most recent additions to the understanding of the biology of IBD was the connection between Lyn kinase and colitis development. By using a DSS mouse model of colitis, researchers demonstrated that systemic Lyn kinase activity is beneficial to the host during colitis development, but the cell specific involvement was not elucidated. Since we recently published that Lyn kinase-specifically in DCs is responsible for the systemic inflammatory effect in lyn-/- mice, we hypothesize that DCs are specifically responsible for the enhanced susceptibility to the colitis in lyn-/- mice. We propose o elucidate the cell-specific role of Lyn by comparing colitis development and progression in DC-specific lyn-/- versus M?-specific lyn-/- versus lyn-/- (systemic) mice in both the IL-10KO and DSS colitis models. We also have evidence showing that Lyn is a regulator of TLR2 signaling via the Syk- PKC?-Card9 pathway leading us to hypothesize that Lyn is a regulator of other surface TLR signaling and cytokine production in DCs. We propose to 1) elucidate Lyn's role in directing other surface TLR signaling, 2) investigate how Lyn affects other cytokine and chemokine production via the Syk-PKC?-Card9 pathway in DCs, and 3) study how Lyn affects the immune response to intestinal pathogens in DCs. Finally, we have preliminary data demonstrating that the Lyn-Syk-PKC?-CARD9 pathway contributes significantly to hyper- production of TNF? in DCs, therefore we hypothesize that genetic or pharmacological manipulation of the Lyn- Syk-PKC?-CARD9 pathway can be used to ameliorate colitis by lowering TNF? production. We propose to 1) reduce IL-10KO and DSS induced colitis in lyn-/- mice by crossing these animals to pkc?-/- and card9-/- mice, 2) prevent or treat colitis in IL-10KO mice or DSS treated wt mice by targeting Lyn kinase with MLR-1023 (Lyn activator). All of the proposed experiments are designed to increase our understanding of the DC-specific role of Lyn kinase in IBD pathogenesis and to expand our overall knowledge of Lyn kinase signaling and biology. We ultimately desire to have our research lead to the generation of therapeutic agents targeting the Lyn-Syk- PKC?-Card9 pathway for IBD treatment in the clinic.