Regulation of Experimental Colitis by Enteric Neurons

项目摘要 炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，是一种慢性和 胃肠道（GI）进行性炎症性疾病最常诊断为 青春期和青年期。虽然已经取得了重大进展，但目前的治疗方法 对于IBD的治疗仍然往往不令人满意，与长期失败和副作用有关。 有必要对这种情况的潜在发病机制和机制进行调查， 确定新的靶点以开发新的治疗策略。自主神经系统 调节胃肠道的关键功能，包括内源性（肠神经系统，ENS）和 肠的外在（交感神经和副交感神经）控制。自主神经麻痹 已经描述了IBD患者的神经功能，一些研究表明ENS 可能在肠道炎症的发展和严重程度中发挥作用。乙酰胆碱（ACh） 已知来自外部副交感神经的神经递质通过以下途径对肠道具有抗炎作用： 胆碱能抗炎通路（CAIP）。然而，尚不清楚乙酰胆碱或其他 源自ENS神经元的神经递质具有类似的作用。初步 在实验中，我们发现实验诱导的结肠炎的严重程度在局灶性结肠炎区域更糟。 ENS消融。因此，我们假设ENS的固有神经元可以产生抗- 因此，本发明人认识到，在结肠中的炎症作用，并且这可以用于治疗应用。到 测试这一点，我们提出了以下目标：（1）确定内在的机制， 肠神经元减轻实验性结肠炎的炎症，并（2）检查ENS是否 细胞移植可以减少IBD小鼠模型中的炎症。我们将使用一种新型IBD 我们最近通过局部注射人 将白喉毒素（DT）局部消融至在ENS中表达DT受体的转基因小鼠中。 所有肠神经元或胆碱能肠神经元将随后诱导结肠炎 确定ENS的抗炎作用（目的1）。然后我们将纯化肠神经元 干细胞、肠神经元和肠胆碱能神经元，并将它们移植到受体中 诱导结肠炎后患有局灶性结肠无神经节细胞症的小鼠。细胞治疗对 检查炎症的严重程度（目的2）。所取得的成果将提供新的 深入了解ENS的抗炎作用，并确定治疗IBD的新策略。

PROJECT SUMMARY Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn disease, is a chronic and progressive inflammatory disorder of the gastrointestinal (GI) tract most often diagnosed in adolescence and young adulthood. While significant progress has been made, current treatments for IBD are still often unsatisfactory, associated with long-term failure and side effects. Investigation into the underlying pathogenesis and mechanisms of this condition are warranted to identify new targets to develop novel treatment strategies. The autonomic nervous system regulates key functions of the GI tract, including both intrinsic (enteric nervous system, ENS) and extrinsic (sympathetic and parasympathetic) control of the intestine. Abnormalities of autonomic nerve function have been described in patients with IBD and several studies suggest that the ENS may play a role in the development and severity of intestinal inflammation. Acetylcholine (ACh) from extrinsic parasympathetic nerves is known to have an anti-inflammatory effect on the gut via the cholinergic anti-inflammatory pathway (CAIP). However, it is unknown whether ACh or other neurotransmitters derived from the neurons of the ENS have a similar role. In preliminary experiments, we find that the severity of experimentally induced colitis is worse in regions of focal ENS ablation. Therefore, we hypothesize that the intrinsic neurons of the ENS can exert an anti- inflammatory effect in the colon and that this can be leveraged for therapeutic applications. To test this, we propose the following aims: (1) to determine the mechanisms by which intrinsic enteric neurons attenuate inflammation in experimental colitis and to (2) examine whether ENS cell transplantation can reduce inflammation in a mouse model of IBD. We will utilize a novel IBD mouse with colonic aganglionosis that we recently developed by local injection of human diphtheria toxin (DT) into transgenic mice that express DT receptor in the ENS. Focal ablation of either all enteric neurons or the cholinergic enteric neurons will be followed by induction of colitis to determine the anti-inflammatory roles of the ENS (Aim 1). We will then purify enteric neuronal stem cells, enteric neurons, and enteric cholinergic neurons and transplant these into recipient mice with focal colonic aganglionosis following induction of colitis. The impact of cell therapy on the severity of inflammation will be examined (Aim 2). The results obtained will provide new insights into the anti-inflammatory role of the ENS and identify new strategies for treating IBD.