Targeting Protein Arginine Deiminases to Prevent Colitis and Colon Cancer

描述(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)]的人患结肠癌的风险很高。IBDS是终生的，大约三分之一的患者在童年时期就开始了。由于对IBD认识的新进展，免疫抑制剂(主要针对TNF1)以及其他生物药物的使用越来越频繁。虽然这种方法改善了大多数中到重度IBD患者的临床状况，但这种积极的策略也有副作用，包括严重感染、癌症和死亡。因此，发现和开发从药物上抑制结肠炎和预防结肠癌的新的治疗策略是当务之急。使用氯代亚胺就是这样一种策略。我们有令人兴奋的数据表明，在几种结肠炎模型中，氯-嘧啶可以抑制结肠炎，重要的是，可以口服治疗/逆转结肠炎。在这里，我们将建立在这些初步数据的基础上，并：(1)测量氯嘧啶的药代动力学/药效学特性，以及测量其在治疗结肠炎方面的稳定性；(2)确定氯-嘧啶是否可以用于预防与结肠炎相关的结肠癌；以及(3)了解预防结肠炎和结肠癌的机制。特别是，我们将重点研究P53介导的效应器T细胞群的凋亡。这项建议意义重大，因为我们已经确定了一种新的炎症调节剂，似乎几乎没有副作用，并针对在慢性结肠炎(CD4？效应器T细胞)。尽管目前尚不清楚氯-嘧啶的最终临床用途，但至少，拟议的研究将验证PADS作为治疗结肠炎的新治疗靶点。结肠炎是一种影响数百万人的疾病，对其成功的无毒治疗是有限的。

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.