People with inflammatory bowel disease [ulcerative colitis (UC) and Crohn's disease (CD)] have a high colon cancer risk. IBDs are life-long, and start in about one third of patients during childhood. Due to recent advances in the understanding of IBD, immunosuppressive agents (mainly against TNF1) as well as other biological drugs are more and more often used. Although this approach has improved the clinical condition of the majority of patients with moderate to severe IBD, this aggressive strategy has side effects, including severe infection, cancer and death. Therefore, the discovery and development of novel therapeutic strategies to suppress colitis and prevent colon cancer pharmacologically are of high priority. The use of Cl-Amidine represents one such strategy. We have exciting data indicating that Cl-Amidine suppresses colitis in several models of colitis, and importantly can be used orally to treat/reverse colitis. Here, we will build on this preliminary data and: (1) measure the pharmacokinetic/pharmacodynamic properties of Cl-amidine, as well as measure its'robustness in the treatment of colitis;(2) identify whether Cl-Amidine can be used to prevent colon cancer associated with colitis;and (3) understand the mechanisms involved in the protection against colitis and colon cancer. In particular, we will focus on p53-mediated apoptosis of the effector T cell population. This proposal is significant because we have identified a novel modulator of inflammation that appears to have few side effects, and targets the population of cells playing a key role in perpetuating chronic colitis (CD4? effector T cells). Although the ultimate clinical utility of Cl-Amidine is as yet unknown, at a minimum, the proposed research will validate the PADs as a novel therapeutic target for the treatment of colitis, a disease that affects millions and for which successful non- toxic treatments are limited.
Current biological therapies of inflammatory bowel disease (IBD;a high colon cancer risk disease) are fraught with side effects, including cancer and death. We have identified a new small molecule that inhibits colitis by specifically targeting the cells that drive colitis;attractive because this results in fewer side effects. Funding toward this project will validate this novel therapeutic target for the treatment of colitis, and the prevention of colon cancer, as a necessary pre-requisite to providing the rationale for testing this compound in clinical trials.
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| Fuhrmann, Jakob; Thompson, Paul R (2016) Protein Arginine Methylation and Citrullination in Epigenetic Regulation. ACS Chem Biol 11:654-68 |
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| Witalison, Erin E; Cui, Xiangli; Causey, Corey P et al. (2015) Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer. Oncotarget 6:36053-62 |
| Knight, Jason S; Subramanian, Venkataraman; O'Dell, Alexander A et al. (2015) Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis 74:2199-206 |
| Witalison, Erin E; Thompson, Paul R; Hofseth, Lorne J (2015) Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with Dysregulation. Curr Drug Targets 16:700-10 |
| Witalison, Erin E; Cui, Xiangli; Hofseth, Anne B et al. (2015) Inhibiting protein arginine deiminases has antioxidant consequences. J Pharmacol Exp Ther 353:64-70 |
| Fuhrmann, Jakob; Clancy, Kathleen W; Thompson, Paul R (2015) Chemical biology of protein arginine modifications in epigenetic regulation. Chem Rev 115:5413-61 |
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