DESCRIPTION (provided by applicant): Numerous studies have shown that TSP1 is a powerful antiangiogenic compound with diverse roles in many physiological and pathological events. TSP1 interacts with and activates members of different pathways regulating cell migration, proliferation and apoptosis. TSP1 expression is observed in a wide variety of normal and tumor cells and in cells of the immunological system, such as macrophages and polymorphonuclear, that are involved in acute and chronic inflammation. Recently we reported that TSP1 deficient (TSP1-/-) mice show aggravation of colitis using the DSS model. TSP1-/- colons also displayed enhanced expression of markers of carcinogenesis. As evidenced on our data and others, TSP1 can modulate the inflammatory response and initiate the carcinogenesis process in IBD. This project's three fundamental goals expand on the findings of current NIH supported research. The first goal is to determine the expression of genes associated to TSP1 in DSS- induced colitis and recognize its specific molecular targets in intestinal inflammation. The unraveling of the TSP1 molecular mechanisms may lead to the discovery and design of new therapeutic strategies for treating IBD. Second, we will characterize and map the genetic pathways associated with TSP1 on the development of colitis-related carcinogenesis. The full understanding of the cellular processes occurring when a normal cell changes to malignant is fundamental for cancer prevention and underscores the importance of analyzing the pro- inflammatory factors modulated by TSP1 and the specific effects of these factors on malignant cell transformation. Finally, this project will evaluate the therapeutic effects of specific TSP1 peptides on inflammation, proliferation, apoptosis and angiogenesis. Most importantly, this project will analyze gene and protein expression of the known, relevant cell signaling pathways involved in such processes. The continuation of this research will certainly contribute to our understanding of the role of TSP1 in cancer and inflammation and the development of new therapeutic ways of managing IBD.
PUBLIC HEALTH RELEVANCE: More than 1.4 million Americans suffer from inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease. Patients with IBD have a high risk of developing colorectal cancer. These chronic and idiopathic diseases seriously degrade the quality of life of afflicted individuals and represent a significant burden on the country's health care system. We are investigating the role of thrombospondin 1 in the development of these diseases and testing specific sequences of this protein as a novel and safe therapy for IBD and colorectal cancer.