METABOLIC CHANGES UNDERLYING 16P11.2 DELETION SYNDROME

项目摘要 我们的建议是基于新陈代谢改变与16p11.2缺失相关的假设 综合征(16pdel)。我们正在采用一种新的方法来确定这种症状和治疗途径。 严重和普遍的精神健康/神经发育综合症，影响1：2000人。删除一个 包括25个基因的染色体间隔与自闭症、智力残疾、癫痫、 多动症、体型过大和运动障碍。所有证据都指向由 两个或多个16p11.2基因的相互作用。引人注目的是，在这个区间内，8/25的基因编码酶或酶 我们的数据表明16p11.2酶FAM57B，a之间存在关键的三向相互作用 神经酰胺合成酶；CDIPT，唯一的磷脂酰肌醇合成酶；ALDOA，一种糖酵解酶。FAM57B是 一个关键的‘Hub’基因，因为它与可接近的全动物斑马鱼中的多个16p11.2同源物相互作用 模特。代谢物分析确定的令人鼓舞的初步数据表明，血脂紊乱是一种 16pdel综合征的重要组成部分。有三个目标，每个目标都基于初步数据，将 人的神经元，包括来自16pdel综合征ips细胞的神经元，与整个动物一起处理 在斑马鱼身上进行测试。第一个目标将确定人类神经元和斑马鱼新陈代谢的变化 大脑，16p11.2酶的突变。第二个目标将确定动物的细胞和行为表型 影响人类神经元和斑马鱼突变体。第三个目标将评估药物调节 突变的表型。这项高额奖励计划将识别导致 并通过挽救牵连的生化途径，为治疗干预提供一条途径。

Project Summary Our proposal is based on the hypothesis that altered metabolism is associated with 16p11.2 deletion syndrome (16pdel). We are taking a novel approach to define symptoms and treatment pathways for this severe and prevalent mental health/neurodevelopmental syndrome, affecting 1:2000 people. Deletion of one chromosomal interval, that includes 25 genes, is tightly associated with autism, intellectual disability, seizures, hyperactivity, large body size and movement disorders. All evidence points to each symptom resulting from interaction of two or more 16p11.2 genes. Strikingly, 8/25 genes in the interval encode enzymes or enzyme modulators, and our data indicates a key three-way interaction between the 16p11.2 enzymes FAM57B, a ceramide synthase; CDIPT, the only phosphatidylinositol synthase and ALDOA, a glycolytic enzyme. fam57b is a pivotal `hub' gene, as it interacts with multiple 16p11.2 homologs in the accessible whole animal zebrafish model. Encouraging preliminary data determined by metabolite profiling implicate lipid disruption as an important component to 16pdel syndrome. There are three Aims, each based on preliminary data that will be addressed in human neurons, including neurons derived from 16pdel syndrome iPS cells, with whole animal tests in the zebrafish. The first Aim will determine changes in metabolism of human neurons and zebrafish brain, mutant for 16p11.2 enzymes. The second aim will determine cellular and behavioral phenotypes in affected human neurons and zebrafish mutants. The third aim will assess pharmacological modulation of mutant phenotypes. This high reward proposal will identify erroneous biochemistry that contributes to the disorder and provide an avenue for therapeutic intervention by rescuing implicated biochemical pathways.