Investigating the cellular and molecular neuropathology of the cerebellum in autism

项目摘要/摘要 自闭症谱系障碍(ASD)是一种常见的、不同类型的诊断，具有行为挑战 在生命的早期发展。小脑是大脑的一部分，在导致自闭症方面起着重要作用。 发病机制，尽管关于生物机制和非典型发育的出现的细节 是不理解的。为了解决这一重大的知识差距，我们将研究约100,000个细胞，以 对确诊为慢性病的患者小脑的分子和细胞表型进行表征 ASD.在目标1中，我们将使用单核rna测序来鉴定身体中的所有细胞类型。 小脑和激光捕获显微解剖专门从小脑皮质分离浦肯野细胞 详细检查此单元格类型。在目标2中，我们将整合现有的批量和单细胞转录数据集 为了推断诊断为霍奇金淋巴瘤的个体小脑细胞表型的时间特异性 ASD.通过整合新的和现有的数据，这项研究将提供关于分子的关键信息 ASD小脑细胞多样性可用于阐明其分子机制 潜在的ASD神经病理。

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.