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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）的消化困难显著降低受影响者及其家人的生活质量。据估计，自闭症目前影响88名儿童中的1名，然而，共同发生的胃肠道（GI）痛苦是研究不足，直到最近才被承认，医疗机构;事实上，目前对ASD相关GI没有统一的治疗策略痛苦我们的目标是确定ASD中GI困扰的机制，作为一种手段，治疗策略为了做到这一点，我们开发了一种最普遍的遗传模型， ASD的形式，McDermid综合征。这种综合征的胃肠道症状包括腹泻，反流，周期性呕吐McDermid综合征是由SHANK 3基因的一个拷贝丢失引起的。基因，我们的团队已经能够在斑马鱼中复制这种情况。我们的斑马鱼模型提供了一种创新的方法来确定shank 3突变的机制，与胃肠道不适症状有关斑马鱼有两个独特的特点，使它们成为理想的这项工作的模型：它们的幼虫是透明的，使我们能够看到它们的GI功能，而它们是透明的。我们可以研究调节回路的发展，以确定那些shank 3突变组织，引起胃肠道不适。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， habitat还支持有针对性的药物筛选，以测试治疗策略。在目标一中，我们测试了引起McDermid综合征的shank 3突变如何影响已知调节GI功能的组织。在第二个目标中，我们测试已知的激素和神经递质是否调节GI功能可以改善shank 3突变鱼的消化能力。有一个巨大的需要，以解决在ASD的GI困扰。这个项目将提高我们对这一点的理解问题，并将为制定解决方案铺平道路。