Regulation of Experimental Colitis by Enteric Neurons

肠神经元对实验性结肠炎的调节

• 批准号: 10393593
• 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/10393593
• 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; gut inflammation; 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.

项目总结 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被诊断为 青春期和青壮年。虽然已经取得了重大进展，但目前的治疗方法 对于IBD的治疗往往仍不令人满意，与长期失败和副作用有关。 有必要对这种疾病的潜在发病机制和机制进行研究 确定新的目标，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，包括固有的(肠道神经系统，ENS)和 对肠道的外在(交感和副交感)控制。自主神经异常 已经描述了IBD患者的神经功能，几项研究表明，ENS 可能在肠道炎症的发展和严重程度中起作用。乙酰胆碱(ACh) 已知来自外源性副交感神经的物质对肠道有抗炎作用 胆碱能抗炎途径(CAIP)。然而，尚不清楚ACh或其他 来自神经元的神经递质也有类似的作用。在预赛中 实验，我们发现实验诱导的结肠炎的严重程度在病灶区域更严重。 ENS消融。因此，我们假设ENS的内源性神经元可以发挥抗病毒作用。 他说，这种药物在结肠炎性反应中起作用，可用于治疗应用。至 为了测试这一点，我们提出了以下目标：(1)确定内在机制 肠神经元减轻实验性结肠炎的炎症反应和(2)检测ENS 细胞移植可以减轻IBD小鼠模型的炎症反应。我们将利用一种新型的IBD 我们最近通过局部注射人的方法培育的结肠性无神经节细胞增多症小鼠 将白喉毒素(DT)导入ENS中表达白喉毒素受体的转基因小鼠。局灶性消融 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)。然后我们将提纯肠道神经元 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 小鼠结肠炎诱导后出现局灶性结肠性无神经节细胞增多症。细胞治疗对人类免疫功能的影响 将检查炎症的严重程度(目标2)。所获得的结果将为我们提供新的 洞察ENS的抗炎作用，并确定治疗IBD的新策略。