Transcriptional signature profiling of IGF1-treated neural cells from idiopathic autistic patients

项目摘要 自闭症谱系障碍(ASD)包括一组复杂的神经发育障碍，影响1/4 美国有68名儿童。ASD在表型和病因上都是不同的，这使它具有挑战性 揭示潜在的遗传/细胞病理生理学，并有效地设计具有广泛应用价值的药物 临床益处。诱导多能干细胞是理解复合体的理想模型 遗传成分较强的疾病，如自闭症。尽管已经为单基因产生了IPSC ASD疾病，在复杂和异质性疾病中疾病特异性发病机制的展示 例如特发性自闭症是目前该领域的一个挑战。 胰岛素样生长因子1(IGF1)最近成为治疗这两种疾病的一种潜在有效的选择 症状性和非症状性ASD。在过去的几年里积累了越来越多的证据 啮齿动物和人类ASD模型都已将IGF1确立为最有前途的ASD治疗方法之一 迄今为止的干预措施。而IGF1在配体结合下游的作用(IGF1受体)已经被 在文献中全面研究了IGF1活性如何导致ASD的治疗康复 在很大程度上仍不为人所知。 这项建议将侧重于了解IGF1-治疗活性的分子机制。 来自自闭症患者的IPSC来源的神经细胞。这将通过执行转录配置文件来实现 IPSC来源的神经细胞来自先前描述的ASD患者队列，这些患者表现出功能性 体外对IGF1处理的反应。神经培养物将在神经元成熟期间或在 将评估和比较IGF1的成熟期及其治疗后对IGF1的分子反应 对神经典型对照的反应。 这项提议将产生一份差异调控基因和分子相互作用的综合清单 这可能会产生关于IGF1在以下背景下的具体下游目标的宝贵信息 ASD患者的神经细胞。此外，在此生成的转录配置文件数据集和分析 该提案将为其他对IGF1下游相互作用感兴趣的研究人员提供独特的资源 并有可能帮助寻找有效的ASD临床干预的候选途径和靶点。

Project Summary Autism spectrum disorders (ASD) comprise a group of complex neurodevelopmental disorders that affect 1 in 68 children in the United States. ASD is phenotypically and etiologically heterogeneous, making it challenging to uncover the underlying genetic / cellular pathophysiology and to efficiently design drugs with widespread clinical benefits. Induced pluripotent stem cells (iPSCs) constitute an ideal model for understanding complex diseases with strong genetic component such as ASD. Although iPSCs have been generated for monogenetic ASD diseases, the demonstration of disease-specific pathogenesis in complex and heterogeneous diseases such as idiopathic ASD is a current challenge in the field. Insulin-Like Growth Factor 1 (IGF1) has recently emerged as a potentially efficient treatment option for both syndromic and non-syndromic forms of ASD. A growing body of evidence accumulated in the past years in both rodent and human ASD models have established IGF1 as one of the most promising ASD therapeutic interventions to date. While IGF1 effects downstream of ligand binding (IGF1 receptor) have been comprehensively studied in the literature, how IGF1 activity may lead to therapeutic recover in the ASD context is still largely unknown. This proposal will focus on understanding the molecular mechanisms underlying IGF1-therapeutic activity in iPSC-derived neural cells from ASD individuals. This will be achieved by performing transcriptional profiling on iPSC-derived neural cells from a previously characterized cohort of ASD patients that show functional response to IGF1 treatment in vitro. The neural cultures will be treated during neuronal maturation or at the mature stage with IGF1 and their molecular responses to IGF1 after treatment will be evaluated and compared to the responses on neurotypical controls. This proposal will generate a comprehensive list of differentially regulated genes and molecular interactions that will potentially produce valuable information about specific downstream targets of IGF1 in the context of ASD patients' neural cells. Additionally, the transcriptional profile dataset and analysis generated in this proposal will provide a unique resource for other researchers interested in IGF1 downstream interactions in ASD and will potentially help finding candidate pathways and targets for effective ASD clinical intervention.