The MET Signaling System,Autism and Gastrointestinal Dysfunction

描述（由申请人提供）：自闭症谱系障碍（ASD）的临床表现是高度复杂和异质性的，除了用于诊断的三个核心行为标准（社会行为，沟通，限制兴趣/重复行为）之外，还存在医疗和精神健康中断。在设计研究策略以了解ASD表达的潜在机制时，经常忽略胃肠道功能障碍（GID）等共同发生的医疗条件。这些不同症状产生的发育机制尚不清楚，但我们假设一些自闭症易感基因编码参与多个系统发育和功能的多效分子。这一独特的假设是基于我们的发现，即编码酪氨酸激酶受体MET的基因携带一个干扰转录的5'常见多态性(C)。总共，来自3个不同实验室的6个独立队列已经确定了这个和另一个在ASD中富集的变体（内含子1）。MET在大脑布线和胃肠道上皮细胞修复中起作用。我们最近对200多个AGRE家族的回顾性研究表明，65%的GID和ASD同时发生的病例中存在C等位基因，而ASD单独存在的比例为58%，普通人群中为47%。这项R21倡议在洛杉矶儿童医院/南加州大学和范德比尔特大学的Monroe Carell Jr儿童医院提出了一项前瞻性研究。在目标1中，我们将在有和没有ASD的儿科人群中描述GID。研究人群将通过诊断儿童功能性胃肠道疾病的标准化工具、儿童胃肠道症状问卷和经验丰富的儿科胃肠病学家的临床敏锐度来详细描述。还将收集营养信息，以确定是否存在与饮食和营养状况相关的功能障碍模式。对ASD中GID的深入表征将为研究人群提供独特的流行病学描述，可能揭示+ASD/+GID组中GI状况的特定模式。在目标2中，我们将把遗传风险发现与可能解释GI和脑功能障碍的生物学变化联系起来。我们将根据两个与ASD相关的MET基因座对所有参与者进行基因分型。我们还将在同一研究人群的外周单核细胞中量化MET蛋白，这是表达MET的主要血细胞类型。我们已经确定了另一组+ASD/+GID受试者的肠道活检，并将利用这些组织直接测量pan-MET和phospho-MET蛋白水平。

DESCRIPTION (provided by applicant): The clinical manifestation of autism spectrum disorder (ASD) is highly complex and heterogeneous, with medical and mental health disruptions beyond the three core behavioral criteria used for diagnosis (social behavior, communication, restricted interests/repetitive behavior). Co-occurring medical conditions, such as gastrointestinal dysfunction (GID), often are overlooked when designing research strategies to understand the mechanisms underlying the expression of ASD. The developmental mechanisms through which such diverse symptoms arise are unknown, but we hypothesize that some autism vulnerability genes encode pleiotropic molecules that participate in the development and function of multiple systems. This unique hypothesis is based on our discovery that the gene encoding the tyrosine kinase receptor MET carries a 5' common polymorphism (C) that disrupts transcription. In total, 6 independent cohorts from 3 different laboratories have identified this and one other variant (intron 1) that is enriched in ASD. MET plays a role in brain wiring and GI epithelial cell repair. Our recent retrospective study in 200+ AGRE families demonstrated that the C allele is represented in 65% of the cases with co-occurring GID and ASD, compared to 58% in ASD alone and 47% in the general population. This R21 initiative proposes a prospective study at Children's Hospital of Los Angeles/USC and the Monroe Carell Jr Children's Hospital at Vanderbilt University. In Aim 1, we will characterize GID in pediatric populations with and without ASD. The study population will be characterized in detail with both a standardized instrument for diagnosing functional GI disorders in children, the Questionnaire on Pediatric Gastrointestinal Symptoms, and with the clinical acumen of an experienced pediatric gastroenterologist. Nutritional information also will be collected to determine whether there are patterns of dysfunction that correlate with dietary and nutritional status. The in-depth characterization of GID in ASD will provide unique epidemiological descriptions of the study population that may reveal specific patterns of GI conditions within the +ASD/+GID group. In Aim 2, we will connect the genetic risk findings with biological changes that may account for GI and brain dysfunction. We will genotype all participants at the two ASD- associated MET loci. We also will quantify MET protein in the same study population in peripheral monocytes, which is the primary blood cell type that expresses MET. We have ascertained gut biopsies from an additional group of +ASD/+GID subjects and will utilize these tissues to directly measure pan-MET and phospho-MET protein levels. PUBLIC HEALTH RELEVANCE: The research proposal will directly investigate relationships between co-occurring medical conditions and ASD, testing a biological hypothesis regarding disruption of MET signaling as a common theme. The studies will provide insight into patient stratification and biomarker identity that may improve diagnosis and treatment.