Neurobiology of Autism With Macrocephaly

母申请的主要目标（R 01 MH 109648 -04，题为“自闭症的神经生物学， 巨头畸形）是为了研究具有大脑体积的ASD的发育改变 （大头畸形）和正常脑大小（正常头畸形），以了解这些 代表ASD的生物学上不同的亚型。为此，我们正在收集和分析 神经生物学措施，转录组和基因调控元件（增强子）的活动， 诱导多能干细胞（iPSC）衍生的类器官，其获自ASD患者， 大头畸形或正常头畸形。在一个初始的基因表达差异和网络分析 一组大头和正常头先证者-对照对表明，超过75%的 先证者和他们未受影响的父亲之间的差异表达基因特异于 大头或正常头组，证实了我们的假设，这些代表了 不同亚型的ASD，并验证我们的方法，分别分析这些集， 并比较他们的神经生物学。然而，功率分析表明，为了 发现90%的预测总数的增强子元素活跃在我们的模型中，我们需要 分析10例额外的大头和7例额外的正常头的主要数据集 先证者-对照对对于大头症患者，已经有8个家庭，需要 只增加了两个家庭。对于正常头的家庭，所有7个需要新的 注册了总之，在这一补充的主持下，我们将招募9个家庭（18 受试者），生成iPSC系，并产生转录组和增强子数据集。因此， 补充申请要求资金完成招聘，生产iPSC线， 生成因COVID大流行而中断的原始数据。多年来 Vaccarino实验室已被证明有能力进行这项研究，正如法庭上的证词所示 Infinity BiologiX LLC的NIMH干细胞资源，共82个原代细胞系和121个 来自患有ASD的家族的iPSC系（NDA收集C1201和C2424）。

Major goals of the parent application (R01 MH109648-04, entitled “Neurobiology of Autism with Macrocephaly) are to investigate developmental alterations in ASD with large brain size (macrocephaly) and normal brain size (normocephaly) in order to understand whether these represent biologically distinct subtypes of ASD. To this end, we are collecting and analyzing neurobiological measures, transcriptome and gene regulatory element (enhancers) activities in induced pluripotent stem cell (iPSC)- derived organoids obtained from ASD patients with macrocephaly or normocephaly. Differential gene expression and network analyses in an initial set of macrocephalic and normocephalic proband-control pairs suggest that more than 75% of differentially expressed genes between probands and their unaffected fathers were specific to the macrocephalic or normocephalic groups, confirming our hypothesis that these represent different subtypes of ASD, and validating our approach to separately analyze these sets of families and compare their neurobiology. However, power analysis indicate that, in order to discover 90% of the predicted total number of enhancer elements active in our model, we need to analyze primary datasets from 10 additional macrocephalic and 7 additional normocephalic proband-control pairs. For macrocephalic individuals, 8 families are already available, requiring the recruitment of only 2 additional families. For normocephalic families, all 7 need to be newly enrolled. All together, under the auspices of this supplement we will recruit 9 families (18 subjects), generate iPSC lines, and produce transcriptome and enhancer datasets. Thus, this supplement application requests funds to complete recruitment, produce iPSC lines, and generate primary data which has been halted by the COVID pandemic. Over the years, the Vaccarino lab has a demonstrated ability to perform this research, as shown by deposition in the NIMH Stem Cell Resource at Infinity BiologiX LLC of a total of 82 primary cell lines and 121 iPSC lines from families with ASD (NDA collections C1201 and C2424).