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）]的人具有高结肠癌风险。IBD是终身的，大约三分之一的患者在儿童时期开始。由于对IBD认识的最新进展，越来越多地使用免疫抑制剂（主要针对TNF 1）以及其他生物药物。虽然这种方法改善了大多数中度至重度IBD患者的临床状况，但这种积极的策略具有副作用，包括严重感染，癌症和死亡。因此，发现和开发新的治疗策略来抑制结肠炎和预防结肠癌复发是高度优先的。Cl-脒的使用代表了这样一种策略。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，我们将基于这些初步数据：（1）测量Cl-脒的药代动力学/药效学特性，以及测量其在结肠炎治疗中的稳健性;（2）确定Cl-脒是否可用于预防与结肠炎相关的结肠癌;以及（3）了解保护结肠炎和结肠癌的机制。特别是，我们将集中在p53介导的效应T细胞群的凋亡。这一建议是重要的，因为我们已经确定了一种新的炎症调节剂，似乎有很少的副作用，并针对在慢性结肠炎（CD 4？效应T细胞）。尽管Cl-脒的最终临床效用尚不清楚，但至少，所提出的研究将验证PAD作为治疗结肠炎的新型治疗靶点，结肠炎是一种影响数百万人的疾病，并且成功的无毒治疗是有限的。 公共卫生相关性：目前炎症性肠病（IBD;结肠癌高风险疾病）的生物疗法充满了副作用，包括癌症和死亡。我们已经确定了一种新的小分子，通过特异性靶向驱动结肠炎的细胞来抑制结肠炎;有吸引力，因为这会导致更少的副作用。对该项目的资助将验证这种用于治疗结肠炎和预防结肠癌的新型治疗靶点，作为在临床试验中测试该化合物的必要前提。

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. PUBLIC HEALTH RELEVANCE: 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.