INTERVENTION OF AUTOIMMUNE DISEASES BY A NOVEL ANTI-INFLAMMATORY MOLECULE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 自身免疫性疾病如系统性红斑狼疮（SLE）、类风湿性关节炎（RA）和炎症性肠病（IBD）是异质性、慢性和复发性炎症性疾病，其对生活质量具有显著影响。尽管有各种各样的原因（例如环境因素，遗传易感性，肠道细菌不平衡），最终结果是异常的免疫反应，反复出现炎症。常规治疗可以减少活动性疾病的时间，并有助于维持缓解，但这些治疗往往带来边际结果，患者变得难治，并有副作用。出于这个原因，仍然需要找到新的治疗策略来减轻自身免疫。精氨酸转化为瓜氨酸（称为脱亚胺的酶促反应）是通过肽基精氨酸脱亚胺酶（PAD）家族酶进行的。这会导致蛋白质的瓜氨酸化，从而改变其功能。最近的证据表明，瓜氨酸是一种炎症依赖性过程。南卡罗来纳州大学的Paul Thompson博士的实验室有新的令人兴奋的数据，显示一种新的PAD抑制剂（Cl-Amidine）降低了RA小鼠模型的发病率并抑制炎症。我们有令人兴奋的初步数据表明PAD水平在IBD小鼠模型和瘙痒小鼠（全身性自身免疫小鼠模型）中升高。有趣的是，PAD 4的遗传多态性最近被报道与结肠炎易感性增加有关，强调了其对这种疾病的重要性。因此，我们的目标是测试的假设，Cl-脒（一种礼物，汤普森博士）减弱自身免疫在这些模型。总的来说，该项目提供了一个独特的机会，将具有抗炎特性的新型化合物（Cl-Amidine）的发现与两位研究人员（Hofseth博士和Matesic博士）的专业知识联系在一起，他们拥有自身免疫和慢性炎症的工作模型。鉴于Cl-脒的新奇和经证实的低毒性，结果有可能：（1）在中等至高影响力的期刊上发表至少两篇论文;（2）导致两名研究人员发起RO 1赠款。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autoimmune diseases like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) are heterogeneous, chronic and relapsing inflammatory conditions that have a significant impact on the quality of life. Despite a wide variety of causes (e.g. environmental factors, genetic susceptibility, imbalanced enteric bacteria), the end-result is an abnormal immune response with repeatedepisodes of inflammation. Conventional treatment can reduce periods of active disease and help to maintain remission, but these treatments often bring marginal results, patients become refractory, and there are side effects. For this reason, there remains a need to find new therapeutic strategies to abate autoimmunity. The conversion of arginine to citrulline (an enzymatic reaction called deimination) is carried out by the peptidyl arginine deiminase (PAD) family of enzymes. This causes citrullination of proteins, which can alter their function. Recent evidence has identified citrullination as an inflammation-dependent process. Dr. Paul Thompson's lab at the University of South Carolina has novel and exciting data showing a novel PAD inhibitor (Cl-Amidine) decreases the incidence and inhibits inflammation in a mouse model of RA. We have exciting preliminary data indicating PAD levels are elevated in a mouse model of IBD, and in itchy mice (a mouse model of systemic autoimmunity). Interestingly, a genetic polymorphism in PAD4 has recently been reported to be associated with increased susceptibility to colitis, underscoring its emerging importance to this disease. We therefore aim to test the hypothesis that Cl-Amidine (a kind gift from Dr. Thompson) abates autoimmunity in these models. Overall, this project offers the unique opportunity to tie together the discovery of a novel compound with proven anti-inflammatory properties (Cl-Amidine) with the expertise of two investigators (Drs. Hofseth and Matesic) whom have working models of autoimmunity and chronic inflammation. Given the novelty and proven low toxicity of Cl-Amidine, results have the potential to: (1) be published as at least two papers in medium to high impact journals; and (2) lead to two investigator initiated RO1 grants.