Targeting Protein Arginine Deiminases to Prevent Colitis and Colon Cancer

描述（由申请人提供）：患有炎症性肠病[溃疡性结肠炎（UC）和克罗恩病（CD）]的人有很高的结肠癌风险。ibd是终生的，大约三分之一的患者在儿童时期发病。由于近年来对IBD认识的进步，免疫抑制剂（主要针对TNF1）以及其他生物药物的使用越来越多。尽管这种方法改善了大多数中重度IBD患者的临床状况，但这种积极的策略有副作用，包括严重感染、癌症和死亡。因此，发现和开发新的治疗策略以抑制结肠炎和从药理学上预防结肠癌是当务之急。cl -脒的使用就是这样一种策略。我们有令人兴奋的数据表明，cl -脒在几种结肠炎模型中抑制结肠炎，重要的是可以口服治疗/逆转结肠炎。在此，我们将以这些初步数据为基础：(1)测量氨基氯胺的药代动力学/药效学特性，并测量其治疗结肠炎的稳健性；(2)确定cl -脒是否可用于预防结肠癌合并结肠炎；(3)了解预防结肠炎和结肠癌的机制。特别是，我们将重点关注p53介导的效应T细胞群的凋亡。这一建议意义重大，因为我们已经确定了一种新的炎症调节剂，似乎没有什么副作用，并且靶向在慢性结肠炎中起关键作用的细胞群。效应T细胞)。虽然cl -脒的最终临床应用尚不清楚，但至少，拟议的研究将验证pad作为治疗结肠炎的新靶点，这种疾病影响数百万人，成功的无毒治疗方法有限。

DESCRIPTION (provided by applicant): 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.