Defining the Role of Enteric Nervous System Dysfunction in Gastrointestinal Motor and Sensory Abnormalities in Down Syndrome

确定肠神经系统功能障碍在唐氏综合症胃肠运动和感觉异常中的作用

• 批准号: 10655819
• 负责人: Jaime Belkind-gerson
• 金额: $ 283.75万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655819
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Animal Experimentation; Autoimmune Diseases; Autoimmunity; Behavior; Biological; Bypass; Childhood; Chromosome abnormality; Chronic; Clinical; Clinical Management; Cognition; Cohort Studies; Colon; Colonic inflammation; Congenital Megacolon; Constipation; Data; Development; Disease; Down Syndrome; Enteral; Enteric Nervous System; Esophageal motility disorders; Exhibits; Food Hypersensitivity; Functional disorder; Gastroesophageal reflux disease; Gastrointestinal Diseases; Gastrointestinal Motility; Genetic; Health; High Prevalence; Hospitalization; Human; Immune; Immune System Diseases; Immunity; Individual; Inflammation; Inflammatory; Injury; Interferon Activation; Intestinal Diseases; Irritable Bowel Syndrome; Knowledge; Kynurenine; Live Birth; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Molecular; Motor; Natural regeneration; Nervous System Physiology; Nervous System Trauma; Neurologic; Neurons; Operative Surgical Procedures; Pathway interactions; Permeability; Persons; Pharmaceutical Preparations; Phenotype; Population; Population Decreases; Predisposition; Prevalence; Probiotics; Quality of life; Reporting; Research; Resected; Risk Factors; Role; Sensory; Sensory Disorders; Small Intestines; Solid; Solid Neoplasm; Testing; Ulcerative Colitis; Variant; Work; cell motility; cohort; colon microbiome; defined contribution; effective therapy; experience; gastrointestinal; gastrointestinal function; gut microbiome; gut microbiota; gut-brain axis; infancy; inflammatory marker; insight; laxative; microbiome; microbiome alteration; motility disorder; mouse model; neonatal period; nervous system disorder; neuron regeneration; neuroregulation; novel; novel diagnostics; novel therapeutic intervention; reduce symptoms; response to injury; therapeutic target

PROJECT SUMMARY. Down syndrome (DS), caused by Trisomy 21 (T21), occurs in ~1 in 700 live births, making the most commonly occurring chromosomal abnormality. Individuals with DS experience a unique disease spectrum, whereby they are protected from some conditions, including solid tumors, and predisposed to others, such as Alzheimer’s disease and autoimmunity. Among the conditions more common in people with DS are gastrointestinal (GI) abnormalities, including esophageal motility disorders, gastro-esophageal reflux, irritable bowel syndrome, small bowel motility disorders, colonic dysmotility, slow transit constipation, and others. However, the molecular mechanisms underlying these conditions remain unclear, creating challenges for their clinical management. Recent work has established that many of these conditions can be caused by damage to the enteric nervous system (ENS). Furthermore, a mouse model of DS was recently shown to have fewer ENS neurons than its wild- type counterparts. Here, we propose that progressive injury to the enteric nervous system (ENS) drives GI motor and sensory abnormalities in DS. The transformative hypothesis of this proposal is that progressive injury to the ENS drives colonic secreto-motor and permeability (SMP) abnormalities in DS leading clinically to chronic constipation. This proposal could illuminate novel aspects of the pathophysiology of GI diseases, which affect more than 50% of individuals with DS. To address these key research gaps and define the mechanisms underlying ENS dysfunction in DS-associated GI disease, we propose a two-part approach: deep-phenotyping in a cohort study of individuals with DS and cause-effect animal research using mouse models of DS. Our Specific Aims are: Specific Aim 1: To expand our ongoing pan-omics cohort study to define associations between markers of inflammation, metabolic dysregulation, and altered GI microbiota, with chronic constipation. Specific Aim 2: To determine the effects of experimental colonic inflammation and microbiome manipulation in a murine model of DS to define the contributions of alterations in inflammation, metabolism, and the microbiome to colonic function. Together, these efforts will not only define the role of ENS dysfunction in key biological and clinical aspects of DS, but also provide the rationale and data to justify the development ENS-based therapies to serve this population by decreasing neuro-intestinal disease.

项目摘要。 由21（T21）引起的唐氏综合症（DS）发生在700个活生生中的〜1中，最常见的是 发生染色体异常。患有DS的人会经历独特的疾病范围 受到某些条件的保护，包括实体瘤，并倾向于其他情况，例如阿尔茨海默氏症 疾病和自身免疫性。在患有DS的人中更常见的条件是胃肠道（GI） 异常，包括食道运动障碍，胃食管反射X，肠易激综合症，小 肠运动障碍，结肠运动障碍，慢速过境便秘等。但是，分子 这些条件下的机制尚不清楚，为其临床管理带来了挑战。 最近的工作已经确定，其中许多条件可能是由于对Enter Sraf的损害造成的 系统（ENS）。此外，最近显示，DS的小鼠模型的ENS神经元比其野生神经元少。 类型对应。在这里，我们建议对肠神经系统（ENS）进行渐进式伤害驱动GI电机 DS中的感觉异常。 该提议的变革性假设是，对ENS驱动的渐进式伤害 DS的秘密运动和渗透率（SMP）异常在临床上导致慢性便秘。这 提案可以阐明GI疾病的病理生理学的新方面，这影响了超过50％ 患有DS的人。 解决这些关键的研究差距并定义与DS相关的ENS功能障碍的基础机制 胃肠病，我们提出了一种分为两部分的方法：在对DS的个体和 使用DS的小鼠模型的因果动物研究。我们的具体目的是： 特定目的1：扩展我们正在进行的泛瘤队列研究以定义标记之间的关联 具有慢性便秘的炎症，代谢失调和胃肠道微生物群的改变。 特定目的2：确定实验性殖民炎症和微生物组的影响 在DS的鼠模型中操纵以定义炎症改变的贡献， 代谢和微生物组到结肠功能。 这些努力共同定义了ENS功能障碍在关键生物学和临床方面的作用 DS，但还提供了基本原理和数据，以证明基于ENS ENS的疗法的合理性 人口通过减少神经肠病。