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， 胃肠道（GI）的进行性炎症性疾病最常被诊断出 青春期和成年。尽管已经取得了重大进展，但目前的治疗 因为IBD通常仍然不满意，与长期失败和副作用有关。 必须对这种情况的潜在发病机理和机制进行调查 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，包括固有的（肠神经系统，ENS）和 肠道外部（交感神经和副交感神经）控制。自主神经异常 在IBD患者中已经描述了神经功能，几项研究表明ENS 可能在肠道炎症的发展和严重程度中发挥作用。乙酰胆碱（ACH） 已知来自外部副交感神经对肠道的抗炎作用 胆碱能抗炎途径（CAIP）。但是，尚不清楚ACH还是其他 来自ENS神经元的神经递质具有相似的作用。在初步 实验，我们发现局灶性区域中实验诱导的结肠炎的严重程度较差 ENS消融。因此，我们假设ENS的固有神经元可以发挥抗 结肠的炎症作用，可以将其用于治疗应用。到 对此进行测试，我们提出以下目的：（1）确定固有的机制 肠神经元减弱了实验性结肠炎的炎症，并检查（2）是否eNS是否 细胞移植可以减少IBD小鼠模型中的炎症。我们将利用一个小说的IBD 我们最近通过局部注射人类开发的结肠诱发的小鼠 白喉毒素（DT）纳入ENS中表达DT受体的转基因小鼠。局部消融 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（AIM 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，并将其移植到受体中 诱导结肠炎后患有局灶性结肠剧型病的小鼠。细胞疗法对 将检查炎症的严重程度（AIM 2）。获得的结果将提供新的 洞悉ENS的抗炎作用，并确定治疗IBD的新策略。