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， 美国68个孩子ASD在表型和病因学上是异质的， 为了揭示潜在的遗传/细胞病理生理学，并有效地设计具有广泛的遗传学特性的药物， 临床获益。诱导性多能干细胞（iPSC）是理解复杂性的理想模型。 具有强烈遗传成分的疾病，如ASD。虽然iPSC已经产生用于单基因遗传 ASD疾病，证明复杂和异质性疾病的疾病特异性发病机制 例如特发性ASD是该领域当前的挑战。 胰岛素样生长因子1（IGF 1）最近已成为一种潜在的有效治疗选择， ASD的综合征和非综合征形式。在过去几年中， 啮齿类动物和人类ASD模型都已确定IGF 1是最有前途的ASD治疗药物之一 干预至今。虽然IGF 1在配体结合（IGF 1受体）下游的作用已经被证实， 在文献中全面研究了IGF 1活性如何导致ASD背景下的治疗恢复 仍是未知数 这项建议将集中在了解IGF 1治疗活性的分子机制， 来自ASD个体的iPSC衍生的神经细胞。这将通过对以下基因进行转录谱分析来实现： 来自先前表征的ASD患者队列的iPSC衍生的神经细胞显示出功能性 对体外IGF 1治疗的反应。神经培养物将在神经元成熟期间或在神经元成熟时进行处理。 将评估和比较两组患者治疗后对IGF 1的分子应答 与正常对照组的反应相对应。 这项建议将产生一个全面的差异调节基因和分子相互作用的清单 这将可能产生有价值的信息，具体的下游目标IGF 1的背景下， 自闭症患者的神经细胞。此外，转录谱数据集和分析中产生的， 该提案将为其他对IGF 1下游相互作用感兴趣的研究人员提供独特的资源， ASD，并可能有助于寻找有效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.