Investigating the cellular and molecular neuropathology of the cerebellum in autism

项目总结/摘要 自闭症谱系障碍（ASD）是一种常见的，异质性的诊断与行为的挑战， 在生命早期发育。小脑是大脑的一部分，在ASD中起着重要作用 发病机制，虽然有关的生物学机制和非典型发展的出现细节 不被理解。为了解决这一重大知识缺口，我们将检查约10万个细胞， 表征被诊断患有以下疾病的个体的小脑中存在的分子和细胞表型： 自闭症在目标1中，我们将使用单核RNA测序来鉴定死后的所有细胞类型。 小脑和激光捕获显微切割，以特异性地分离小脑皮质中的浦肯野细胞， 详细检查这种细胞类型。在目标2中，我们将整合现有的批量和单细胞转录数据集 以推断诊断为小脑疾病的个体的小脑中存在的细胞表型的时间特异性， 自闭症通过整合新的和现有的数据，这项研究将提供有关分子生物学的关键信息。 和小脑的细胞多样性，可用于阐明ASD的分子机制 潜在的ASD神经病理学

PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a common, heterogeneous diagnosis with behavioral challenges that develop early in life. The cerebellum is one part of the brain that has an important role in contributing to ASD pathogenesis, though details regarding the biological mechanisms and the emergence of atypical development is not understood. To address this significant gap in knowledge, we will examine ~100,000 individual cells to characterize the molecular and cellular phenotypes present in the cerebellum of individuals diagnosed with ASD. In Aim 1, we will use single-nucleus RNA-sequencing to identify all cell types in the postmortem cerebellum and laser capture microdissection to specifically isolate Purkinje cells from the cerebellar cortex to examine this cell type in detail. In Aim 2, we will integrate existing bulk and single-cell transcriptional datasets to infer the temporal specificity of cellular phenotypes present in the cerebellum of individuals diagnosed with ASD. By integrating new and existing data, this study will provide critical information regarding the molecular and cellular diversity of the cerebellum in ASD that can be used to elucidate the molecular mechanisms underlying ASD neuropathology.