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Regulation of Experimental Colitis by Enteric Neurons

肠神经元对实验性结肠炎的调节

基本信息

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
项目类别：
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&apos 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

项目摘要

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