The MET Signaling System,Autism and Gastrointestinal Dysfunction

描述(申请人提供)：自闭症谱系障碍(ASD)的临床表现高度复杂和多样化，医疗和精神健康中断超出了用于诊断的三个核心行为标准(社交行为、交流、受限兴趣/重复行为)。在设计研究策略以了解ASD表达的潜在机制时，通常忽略了共同发生的疾病，如胃肠功能障碍(GID)。出现这种不同症状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多效性分子，参与多种系统的发育和功能。这一独特的假说是基于我们的发现，即编码酪氨酸激酶受体MET的基因带有5‘常见的多态(C)，会扰乱转录。总共，来自3个不同实验室的6个独立队列已经确定了该基因和另一个富含ASD的变异体(内含子1)。MET在大脑连接和胃肠道上皮细胞修复中发挥作用。我们最近对200多个AGRE家系进行的回顾性研究表明，C等位基因在65%的GID和ASD共存的病例中存在，而在单纯ASD和普通人群中，这一比例分别为58%和47%。这项R21倡议计划在洛杉矶儿童医院/南加州大学和范德比尔特大学的小门罗卡瑞尔儿童医院进行一项前瞻性研究。在目标1中，我们将描述患有和不患有ASD的儿科人群中GID的特征。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、关于儿童胃肠道症状的问卷以及经验丰富的儿科胃肠病专家的临床敏锐性来详细描述。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。ASD中GID的深入特征将提供对研究人群的独特流行病学描述，可能揭示+ASD/+GID组中胃肠道疾病的特定模式。在目标2中，我们将把遗传风险发现与可能导致胃肠道疾病和大脑功能障碍的生物学变化联系起来。我们将在两个与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中量化外周单核细胞中的MET蛋白，这是表达MET的主要血细胞类型。我们已经确定了另外一组+ASD/+GID受试者的肠道活检组织，并将利用这些组织直接测量PAN-MET和磷酸化MET蛋白水平。 公共卫生相关性：该研究提案将直接调查共同发生的医疗条件和自闭症之间的关系，测试关于MET信号中断作为共同主题的生物学假说。这些研究将提供对患者分层和生物标记物身份的洞察，这可能会改善诊断和治疗。

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.