Ulcerative Colitis (UC) is an idiopathic inflammatory disease of the large intestine that is quite common in the United States and other Western countries. Patients with UC are at greater risk of developing colorectal adenocarcinoma (AC) than the general population. However, the mechanisms involved in the UC-dysplasia- cancer sequence are still unclear. Recent clinical studies have shown that TSP-1 has an important role in AC. ApcMin+ mice that develop multiple intestinal adenomas and carcinomas have shown an increase of tumor growth and invasion when they are TSP-1 deficient. TSP-1 has key functions in inflammation, which is assumed to be the primary cause for carcinogenesis in UC. ? ? The overall objective of this project is to determine the in vivo role of thrombospondin (TSP-1) in inflammation-UC-driven colorectal carcinogenesis. Mice lacking TSP-1 and WT will be challenged using the dextran sulfate sodium (DSS) induced model for UC. Also, the therapeutics effects of TSP derived-peptides n UC will be investigated using the DSS model. This approach is a unique way to analyze in a mechanistic fashion the in vivo functions of TSP-1 in inflammation and inflammation-related carcinogenesis.
The specific aims of this study are: to analyze the temporal-spatial expression of TSP-1 on DSS -induced colitis; to characterize and grade inflammation and dysplasia UC-related in TSP-1 deficient mice; and finally, to investigate the efficacy of TSP-1 derived-peptides on inhibiting the UC inflammation-carcinogenesis progression. ? ? UC is a chronic ulceration of the intestines with an incidence of 1 in 1000 persons in western countries. Still, there is no safe treatment for this costly disease. This proposal will investigate the causes and mechanisms involved in UC in order to develop alternative therapies. ? ?
