Anti-inflammatory Nicotinic Agonists for Therapy of Ulcerative Colitis

描述（由申请人提供）：溃疡性结肠炎（UC）是一种慢性组织破坏性疾病，其中细胞炎症和炎症因子最终导致结肠粘膜损伤。目前还没有有效的治疗方法，虽然标准疗法可以改善一些患者的症状，但它们对大量患者无效，还可能导致严重的副作用。因此，需要新的治疗方法来抑制UC患者的不适当和夸大的炎症反应。这种应用将开发的新的治疗靶点是基于最近对“炎症反流”的阐明，其中神经系统通过迷走神经通过释放乙酰胆碱来调节免疫反应，乙酰胆碱与巨噬细胞a7烟碱乙酰胆碱受体nAChR结合，从而抑制炎症细胞因子的产生。本提案的目标是评估一组选择性a7烟碱乙酰胆碱受体的部分激动剂，以确定进一步临床前开发的最佳候选药物。GTS-21及其三种生物活性代谢物将在体内评估其改善奥扎索龙诱导的小鼠结肠炎模型（类似于人类UC）疾病症状发展和结肠病理改变的能力。药物将在预防和治疗两种方案中进行测试（在结肠炎开始后给药）。药物疗效将通过体重减轻、粪便一致性和血液、结肠组织病理学和结肠组织中髓过氧化物酶的含量来监测。为了研究其作用机制，我们将验证GTS化合物将调节炎症结肠和分离的单核细胞中致病性和/或保护性细胞因子的产生的假设。这项研究的结果将决定进一步临床前和临床开发的最佳候选药物。由于a7 nAChR激动剂会抑制多种炎症细胞因子的产生，这些炎症细胞因子至少在一定程度上导致结肠黏膜的损伤，因此这种治疗方法应该比其他仅针对一种细胞因子的生物疗法更有效。最终，这项工作将为溃疡性结肠炎患者开发一种新的治疗方案，该方案基于一种新的抗炎途径，可能优于当前的治疗方法。公共卫生相关性：这项工作将为溃疡性结肠炎患者开发一种新的治疗选择，该治疗选择基于一种新的抗炎途径，可能优于当前的治疗方法。

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is a chronic tissue-destructive disease in which cellular inflammation and inflammatory cytokines ultimately lead to damage of the colonic mucosa. There is no effective cure, and while standard therapies can ameliorate symptoms in some patients, they are not effective in a significant number of patients and can also cause severe side effects. Consequently, new therapeutic approaches are needed to inhibit the inappropriate and exaggerated inflammatory response in UC patients. The new therapeutic target that this application will develop is based on the recent elucidation of the "inflammatory reflux" in which the nervous system through the vagus nerve regulates immune responses by release of acetylcholine which binds to macrophage a7 nicotinic acetylcholine receptors nAChR resulting in inhibition of inflammatory cytokine production. The goal of this proposal is to evaluate a panel of partial agonists selective for the a7 nicotinic acetylcholine receptor to determine the best drug candidate for further preclinical development. GTS-21 and its three biologically active metabolites will be evaluated in vivo for their ability to ameliorate development of disease symptoms and colon pathological changes in the murine ozaxolone-induced colitis model, which resembles human UC. Drugs will be tested in both prophylactic and therapeutic (administered after initiation of colitis) protocols. Drug efficacy will be monitored by weight loss, stool consistency and presence of blood, histopathology of the colon, and colon tissue content of myeloperoxidase. To investigate the mechanism of action, we will test the hypothesis that the GTS compounds will modulate the production of pathogenic and/or protective cytokines in the inflamed colon and isolated mononuclear cells. The results of this study will determine the best drug candidate for further preclinical and clinical development. Because the a7 nAChR agonists will inhibit production of multiple inflammatory cytokines known to be responsible, at least in part, for damage to colonic mucosa, this therapeutic approach should be more effective than other biological therapies that target only one cytokine. Ultimately this work will develop a new therapeutic option for ulcerative colitis patients that is based on a novel anti-inflammatory pathway that may be superior to current treatments. PUBLIC HEALTH RELEVANCE: This work will develop a new therapeutic option for ulcerative colitis patients that is based on a novel anti-inflammatory pathway that may be superior to current therapies.