Gastrointestinal Comorbidities in Autism Spectrum Disorders

通常伴随自闭症谱系障碍(ASD)的消化不良会显著降低 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， 然而，共同发生的胃肠道(GI)痛苦还没有得到充分的研究，直到最近才被 医疗机构；事实上，目前还没有针对ASD相关GI的统一治疗策略 苦恼。我们的目标是确定ASD患者胃肠道痛苦的潜在机制，以此作为一种手段来建议有效的 治疗策略。为了做到这一点，我们开发了斑马鱼模型，其中最流行的遗传基因之一 各种类型的自闭症，费伦·麦克德米德综合征。这种综合征的胃肠道症状包括腹泻、反流和 周期性呕吐。已知的费兰-麦克德米德综合征是由SHANK3基因的一个副本丢失引起的 基因，我们的团队已经能够在斑马鱼身上复制这种情况。 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胃肠道功能正在进行中，而它们 仍然活着；我们可以研究调节电路的发展，以识别那些 产生肠胃不适。此外，斑马鱼与人类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这两种情况。斑马鱼的体型小，水生 人居中心还支持有针对性的药理筛选，以测试治疗策略。 在第一个目标中，我们测试了导致费兰-麦克德米德综合征的SHANK3突变是如何影响 已知调节胃肠道功能的组织。在第二个目标中，我们测试荷尔蒙和神经递质是否已知 调节GI功能可以改善SHANK3突变鱼的消化。 在ASD中有极大的需求来解决GI的困扰。这个项目将提高我们对这一点的理解 这是一个很大的问题，并将为开发解决方案铺平道路。

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.