Regulation of Experimental Colitis by Enteric Neurons

肠神经元对实验性结肠炎的调节

• 批准号: 10195754
• 负责人: Ryo Hotta
• 金额: $ 8.26万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195754
• 关键词: Ablation; Acetylcholine; Adolescence; Affect; Anti-Cholinergics; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Autonomic nervous system; Biological Models; Cell Therapy; Cell Transplantation; Cells; Chronic; Colitis; Colon; Colonic Aganglionosis; Congenital Megacolon; Crohn' s disease; Development; Diagnosis; Digestive System Disorders; Diphtheria Toxin; Disease; Enteral; Enteric Nervous System; Exhibits; Experimental Models; Failure; Gastrointestinal tract structure; Goals; Human; Immunomodulators; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injections; Intestines; Investigation; Length; Mediating; Mesenchymal Stem Cells; Modeling; Mus; Myenteric Plexus; Nerve; Neuraxis; Neuroglia; Neurons; Neurotransmitters; Output; Pathogenesis; Pathway interactions; Patients; Play; Predisposition; Procedures; Regulation; Research; Role; Sensory; Severities; Spleen; Submucous Plexus; T memory cell; Testing; Therapeutic; Transgenic Mice; Transplantation; Ulcerative Colitis; alpha-bungarotoxin receptor; autonomic nerve; base; cholinergic; cholinergic neuron; cost; diphtheria toxin receptor; enteric neuropathy; experimental study; gastrointestinal function; inflammatory disease of the intestine; insight; macrophage; mouse model; nerve stem cell; nerve supply; neurotrophic factor; novel; novel therapeutic intervention; postnatal; prevent; response; side effect; stem; stem cell therapy; stem cells; therapeutic evaluation; therapeutic target; treatment strategy; young adult

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.

项目概要 炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，是一种慢性、慢性疾病。 进行性胃肠道 (GI) 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 IBD 的治疗效果仍然常常不令人满意，与长期失败和副作用相关。 有必要调查这种情况的潜在发病机制和机制 确定新目标以制定新的治疗策略。自主神经系统 调节胃肠道的关键功能，包括内在功能（肠神经系统，ENS）和 肠道的外在（交感神经和副交感神经）控制。自律神经异常 IBD 患者的神经功能已被描述，多项研究表明 ENS 可能在肠道炎症的发生和严重程度中发挥作用。乙酰胆碱 (ACh) 已知来自外在副交感神经的物质对肠道具有抗炎作用 胆碱能抗炎途径（CAIP）。然而，尚不清楚是否是 ACh 或其他 来自 ENS 神经元的神经递质也具有类似的作用。在初步 实验中，我们发现实验诱发的结肠炎的严重程度在局灶性区域更严重 ENS 消融。因此，我们假设 ENS 的内在神经元可以发挥抗- 结肠中的炎症效应，这可以用于治疗应用。到 对此进行测试，我们提出以下目标：（1）确定内在机制 肠神经元减轻实验性结肠炎中的炎症并（2）检查 ENS 是否 细胞移植可以减轻 IBD 小鼠模型的炎症。我们将利用一种新型 IBD 患有结肠无神经节细胞病的小鼠，我们最近通过局部注射人 将白喉毒素 (DT) 注入在 ENS 中表达 DT 受体的转基因小鼠中。局灶消融 所有肠神经元或胆碱能肠神经元都会诱发结肠炎 确定 ENS 的抗炎作用（目标 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体内 诱发结肠炎后患有局灶性结肠无神经节细胞病的小鼠。细胞治疗的影响 将检查炎症的严重程度（目标 2）。所获得的结果将提供新的 深入了解 ENS 的抗炎作用并确定治疗 IBD 的新策略。