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

项目总结。 由21三体(T21)引起的唐氏综合征(DS)，每700名活产儿中就有1名发生，使最常见的 发生染色体异常的。患有DS的人会经历一种独特的疾病谱，由此他们 对某些疾病有保护作用，包括实体瘤，但容易患上其他疾病，如阿尔茨海默氏症 疾病和自身免疫。在DS患者中，更常见的疾病是胃肠道(GI) 异常，包括食道动力障碍，胃-食道反流，肠易激综合征，小 肠动力障碍、结肠动力障碍、慢传输性便秘等。然而，分子 这些情况背后的机制尚不清楚，这给它们的临床管理带来了挑战。 最近的研究表明，这些情况中的许多都可以由肠道神经受损引起。 系统(ENS)。此外，最近发现，一种DS小鼠模型的ENS神经元比其野生模型的ENS神经元要少。 键入对应物。在这里，我们认为进行性损伤的肠道神经系统(Ens)驱动胃肠道运动。 以及DS的感觉异常。 这一提议的变革性假设是，对ENS的进行性损伤驱动结肠 DS的分泌-运动和通透性(SMP)异常可导致慢性便秘。这 该提案可以阐明胃肠道疾病的病理生理学的新方面，这些疾病影响到超过50%的 患有DS的个体。 为了解决这些关键的研究差距，并确定DS相关的ENS功能障碍的机制 对于胃肠道疾病，我们提出了一个由两部分组成的方法：在DS和DS患者的队列研究中进行深度表型分析 使用DS小鼠模型进行因果动物研究。我们的具体目标是： 具体目标1：扩大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区系改变，并伴有慢性便秘。 特定目的2：确定实验性结肠炎和微生物群的影响 在DS小鼠模型中进行操纵，以确定炎症变化的贡献， 新陈代谢，以及微生物群对结肠的作用。 总而言之，这些努力不仅将定义ENS功能障碍在关键生物学和临床方面的作用 DS，但也提供了理论基础和数据来证明开发基于ENS的疗法来服务于此 通过减少神经性肠道疾病来减少人口。

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.