Targeting Protein Arginine Deiminases to Prevent Colitis and Colon Cancer

靶向蛋白质精氨酸脱亚胺酶预防结肠炎和结肠癌

基本信息

批准号：
8279224
负责人：
Lorne J Hofseth
金额：
$ 33.2万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8279224
关键词：
Address Adoptive Transfer Adverse effects Affect Amidines Animal Experiments Apoptosis Apoptotic Automobile Driving Basic Science Biological Biological Response Modifier Therapy C57BL/6 Mouse CD4 Positive T Lymphocytes Cell division Cells Cessation of life Childhood Chronic Clinical Clinical Trials Colitis Colon Adenocarcinoma Colon Carcinoma Complement Consensus Crohn&apos s disease Data Dependence Development Disease Dose Drug Kinetics Enzymes Funding Goals IL2RA gene Immune Immunosuppressive Agents In Vitro Induction of Apoptosis Infection Inflammation Inflammatory Inflammatory Bowel Diseases Life Malignant Neoplasms Measures Mediating Modeling Molecular Mus Oral Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Play Population Prevention Process Property Protein-arginine deiminase Rag1 Mouse Research Resistance Role Small Interfering RNA T-Lymphocyte Target Populations Testing Therapeutic Treatment Protocols Ulcerative Colitis base cancer risk conventional therapy efficacy testing improved in vivo inhibitor/antagonist mouse model new therapeutic target novel novel therapeutics prevent research study small molecule treatment strategy

Address Adoptive Transfer Adverse effects Affect Amidines Animal Experiments Apoptosis Apoptotic Automobile Driving Basic Science Biological Biological Response Modifier Therapy C57BL/6 Mouse CD4 Positive T Lymphocytes Cell division Cells Cessation of life Childhood Chronic Clinical Clinical Trials Colitis Colon Adenocarcinoma Colon Carcinoma Complement Consensus Crohn&apos s disease Data Dependence Development Disease Dose Drug Kinetics Enzymes Funding Goals IL2RA gene Immune Immunosuppressive Agents In Vitro Induction of Apoptosis Infection Inflammation Inflammatory Inflammatory Bowel Diseases Life Malignant Neoplasms Measures Mediating Modeling Molecular Mus Oral Outcome Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Play Population Prevention Process Property Protein-arginine deiminase Rag1 Mouse Research Resistance Role Small Interfering RNA T-Lymphocyte Target Populations Testing Therapeutic Treatment Protocols Ulcerative Colitis base cancer risk conventional therapy efficacy testing improved in vivo inhibitor/antagonist mouse model new therapeutic target novel novel therapeutics prevent research study small molecule treatment strategy

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项目摘要

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.

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）]的患者具有很高的结肠癌风险。 IBD是终身的，在童年时期约有三分之一的患者开始。由于对IBD的了解最近的进步，免疫抑制剂（主要是针对TNF1）以及其他生物药物越来越多地使用。尽管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，包括严重的感染，癌症和死亡。因此，在抑制结肠炎和预防结肠癌药理的新型治疗策略的发现和发展是高度的。 Cl-酰胺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-氨基抑制几种结肠炎模型中的结肠炎，重要的是可以口服治疗/逆转结肠炎。在这里，我们将基于此初步数据，并且：（1）测量Cl-氨基的药代动力学/药效学特性，并测量其在治疗结肠炎方面的鲁棒性；（2）确定是否可以使用Cl-酰胺定来预防与结肠炎相关的结肠癌；（3）了解保护结肠炎和结肠癌涉及的机制。特别是，我们将重点关注效应T细胞群的P53介导的凋亡。该提议很重要，因为我们已经确定了一种新型的炎症调节剂，该调节剂似乎几乎没有副作用，并且针对细胞的群体在永久性慢性结肠炎（CD4？效应T细胞）中起关键作用。尽管Cl-氨基氨酸的最终临床实用性尚未清楚，但至少尚不清楚，拟议的研究将验证垫子作为治疗结肠炎的新型治疗靶标，这种疾病会影响数百万，并且成功的非毒性治疗受到限制。