Gastrointestinal Comorbidities in Autism Spectrum Disorders

自闭症谱系障碍的胃肠道合并症

基本信息

批准号：
9528152
负责人：
Julia Eve Dallman
金额：
$ 21.77万
依托单位：
UNIVERSITY OF MIAMI CORAL GABLES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-11 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9528152
关键词：
Acetylcholine Address Affect Afferent Neurons Animal Model Antibodies Autistic Disorder Biological Assay Brain Bypass Cell Nucleus Cerebellum Characteristics Child Collaborations Comorbidity DNA Sequence Alteration Data Defect Development Diarrhea Digestion Distress Drug Screening Embryo Ensure Enteral Family Fertilization Fishes Functional disorder Gastrointestinal Motility Gastrointestinal tract structure Genes Genetic Genetic Diseases Genetic Screening Goals Habitats Histologic Hormones Hour Human In Situ Hybridization Individual Larva Life Link Medical Mission Modeling Molecular Morphology Motor Mutation Nervous system structure Neurons Neurotransmitters Nitrous Oxide Nodose Ganglion Other Genetics Outcome Periodicity Pharmacology Phelan-McDermid syndrome Phenotype Process Public Health Quality of life RNA Receptor Signaling Reflux Regulatory Pathway Secondary to Serotonin Signal Pathway Signal Transduction Structure Syndrome Tachykinin Testing Tissues Transgenic Organisms Treatment Efficacy United States National Institutes of Health Visceral Vomiting Work Zebrafish autism spectrum disorder cell motility chemical genetics clinically relevant gastrointestinal gastrointestinal function gastrointestinal symptom ghrelin gut-brain axis hindbrain improved in vivo innovation insight locus ceruleus structure motilin mutant neurodevelopment therapeutic evaluation treatment strategy

项目摘要

The digestive distress that commonly accompanies Autism Spectrum Disorders (ASDs) significantly degrades the quality of life of those affected and their families. ASDs are currently estimated to impact 1 in 88 children, and yet the co-occurring gastrointestinal (GI) distress is understudied, having only recently been recognized by the medical establishment; in fact, there are currently no unified treatment strategies for ASD-linked GI distress. Our goal is to identify the mechanisms that underlie GI distress in ASD as a means to suggest effective therapeutic strategies. To do this, we have developed zebrafish models of one of the most prevalent genetic forms of ASD, Phelan McDermid Syndrome. This syndrome's GI symptoms include diarrhea, reflux, and cyclical vomiting. Phelan McDermid Syndrome is known to be caused by loss of one copy of the SHANK3 gene, a condition our team has been able to replicate in zebrafish. Our zebrafish model provides an innovative way to determine the mechanisms by which shank3 mutations are related to the symptoms of GI distress. Zebrafish have two unique characteristics that make them an ideal model for this work: their larvae are transparent, allowing us to see their GI function in process, while they are still alive; and we can study the development of regulatory circuits to identify those shank3 mutant tissues that produce GI distress. In addition, zebrafish and human nervous systems and GI tracts are remarkably similar, suggesting that the mechanisms we discover will be applicable to both. The zebrafish's small size and aquatic habitat also support targeted pharmacological screens to test therapeutic strategies. In aim one, we test how the shank3 mutations that cause Phelan McDermid Syndrome affect the development of tissues known to regulate GI function. In aim two, we test whether hormones and neurotransmitters known to regulate GI function can improve digestion in the shank3 mutant fish. There is a tremendous need to address GI distress in ASD. This project will improve our understanding of this problem and will pave the way for developing solutions.

通常伴随自闭症谱系障碍 (ASD) 的消化不良症状显着降低受影响者及其家人的生活质量。目前估计每 88 名儿童中就有 1 人患有自闭症谱系障碍 (ASD)，然而，同时发生的胃肠道 (GI) 不适尚未得到充分研究，直到最近才被人们认识到医疗机构；事实上，目前对于自闭症谱系障碍（ASD）相关的胃肠道疾病还没有统一的治疗策略苦恼。我们的目标是确定自闭症谱系障碍中胃肠道不适的机制，以此作为建议有效的方法治疗策略。为此，我们开发了最流行的遗传之一的斑马鱼模型自闭症谱系障碍（ASD）的各种形式，费兰·麦克德米德综合症。该综合征的胃肠道症状包括腹泻、反流和周期性呕吐。已知费兰·麦克德米德综合症是由于丢失一份 SHANK3 造成的基因，我们的团队已经能够在斑马鱼中复制这种条件。我们的斑马鱼模型提供了一种创新方法来确定 shank3 突变的机制与胃肠道不适的症状有关。斑马鱼有两个独特的特征，使它们成为理想的选择这项工作的模型：它们的幼虫是透明的，使我们能够看到它们的胃肠道功能，而它们是还活着；我们可以研究调节回路的发展来识别那些 shank3 突变组织产生胃肠道不适。此外，斑马鱼和人类的神经系统和胃肠道非常相似，这表明我们发现的机制将适用于两者。斑马鱼体型小，水生栖息地还支持有针对性的药理学筛选来测试治疗策略。在目标一中，我们测试了导致费兰·麦克德米德综合征的 shank3 突变如何影响已知调节胃肠道功能的组织。在目标二中，我们测试是否已知激素和神经递质调节胃肠道功能可以改善shank3突变鱼的消化能力。迫切需要解决自闭症谱系障碍患者的胃肠道不适问题。这个项目将加深我们对此的理解问题，并将为制定解决方案铺平道路。