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

基本信息

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
项目类别：
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&apos 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

项目摘要

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。唐氏综合症 (DS) 由 21 三体 (T21) 引起，大约每 700 名活产儿中就有 1 人发生，是最常见的唐氏综合症 (DS) DS 患者患有独特的疾病谱，因此他们患有染色体异常。免受某些疾病（包括实体瘤）的影响，并易患其他疾病（例如阿尔茨海默病） DS 患者更常见的疾病包括胃肠道 (GI)。异常，包括食管动力障碍、胃食管反流、肠易激综合征、小然而，肠蠕动障碍、结肠蠕动障碍、慢传输性便秘等。这些病症背后的机制仍不清楚，这给临床管理带来了挑战。最近的研究表明，许多这些情况可能是由肠神经系统损伤引起的此外，最近发现 DS 小鼠模型的 ENS 神经元比其野生型要少。在这里，我们提出肠神经系统（ENS）的进行性损伤驱动胃肠道运动。 DS 中的感觉异常。该提案的变革性假设是 ENS 的渐进性损伤会导致结肠 DS 的分泌运动和渗透性 (SMP) 异常在临床上导致慢性便秘。该提案可以阐明胃肠道疾病病理生理学的新方面，这些疾病影响超过 50% DS 患者。为了解决这些关键的研究空白并定义 DS 相关的 ENS 功能障碍的机制胃肠道疾病，我们提出了一个由两部分组成的方法：对患有 DS 和使用 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、胃肠道微生物群改变以及慢性便秘。具体目标 2：确定实验性结肠炎症和微生物组的影响在 DS 小鼠模型中进行操作以确定炎症改变的贡献，新陈代谢，以及微生物组对结肠功能的影响。总之，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，还提供了理由和数据来证明基于 ENS 的疗法的开发是合理的通过减少神经肠道疾病来减少人口。