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

项目摘要。 唐氏综合征（DS）由21三体（T21）引起，约700例活产婴儿中有1例发生，是最常见的先天性心脏病。 发生染色体异常。患有DS的个体经历了独特的疾病谱， 在某些情况下受到保护，包括实体瘤，并易患其他疾病，如阿尔茨海默氏症 疾病和自身免疫。在DS患者中更常见的情况是胃肠道（GI） 异常，包括食管动力障碍、胃食管反流、肠易激综合征、小 肠运动障碍、结肠运动障碍、慢传输型便秘等。然而，分子 这些病症的潜在机制仍不清楚，这为其临床管理带来了挑战。 最近的工作已经确定，这些疾病中的许多可以由肠神经损伤引起。 系统（ENS）。此外，最近显示DS小鼠模型的ENS神经元比其野生型少， 类型对应物。在这里，我们提出肠神经系统（ENS）的进行性损伤驱动GI运动 和感觉异常 该提议的变革性假设是ENS的进行性损伤驱动结肠 DS中的分泌运动和渗透性（SMP）异常在临床上导致慢性便秘。这 这项提案可以阐明胃肠道疾病病理生理学的新方面，胃肠道疾病影响了50%以上的人。 个人DS 为了解决这些关键的研究空白，并确定在DS相关的ENS功能障碍的机制， GI疾病，我们提出了一个两部分的方法：在DS个体的队列研究中进行深度表型分析， 使用DS小鼠模型的因果动物研究。我们的具体目标是： 具体目标1：扩展我们正在进行的泛组学队列研究，以确定标记物之间的关联 炎症、代谢失调和胃肠道微生物群改变，伴有慢性便秘。 具体目标2：确定实验性结肠炎症和微生物组的影响 在DS的鼠模型中进行操作以确定炎症改变的贡献， 代谢和微生物组对结肠功能的影响。 总之，这些努力不仅将确定ENS功能障碍在关键生物学和临床方面的作用， DS，但也提供了理由和数据，以证明开发基于ENS的治疗来服务于此 减少神经性肠道疾病。

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.