Investigating the cellular and molecular neuropathology of the cerebellum in autism

研究自闭症小脑的细胞和分子神经病理学

基本信息

批准号：
10195945
负责人：
Kimberly Anne Aldinger
金额：
$ 28.52万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-03 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10195945
关键词：
Address Adult Anatomy Autopsy Bar Codes Behavioral Biological Biological Models Brain Brain Diseases Cell Fraction Cell Nucleus Cell Separation Cells Cerebellar Cortex Cerebellar Diseases Cerebellum Clinical Computer Analysis Cytoplasmic Granules Data Data Set Detection Development Diagnosis Foundations Functional disorder Gene Expression Gene Expression Profile Genetic Transcription Genomics Human In Situ Individual Knowledge Life Masks Molecular Molecular Abnormality Molecular Profiling Neurodevelopmental Disorder Neurons Pathogenesis Phenotype Population Protein Isoforms Purkinje Cells Role Sampling Specificity Split-Pool Ligation Transcriptome sequencing Therapeutic Tissue-Specific Gene Expression Tissues autism spectrum disorder brain tissue cell type combinatorial data resource differential expression disorder control indexing individuals with autism spectrum disorder laser capture microdissection mouse model neuropathology postnatal prenatal preservation transcriptome sequencing transcriptomics

项目摘要

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.

项目概要/摘要自闭症谱系障碍 (ASD) 是一种常见的异质性诊断，其行为挑战在生命早期发育。小脑是大脑的一部分，在导致自闭症谱系障碍（ASD）方面发挥着重要作用发病机制，尽管有关生物学机制和非典型发育出现的详细信息不明白。为了解决这一巨大的知识差距，我们将检查约 100,000 个单个细胞，以描述被诊断患有此病的个体小脑中存在的分子和细胞表型自闭症谱系障碍。在目标 1 中，我们将使用单核 RNA 测序来识别死后的所有细胞类型小脑和激光捕获显微切割，从小脑皮质中特异性分离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推断被诊断患有以下疾病的个体小脑中存在的细胞表型的时间特异性自闭症谱系障碍。通过整合新的和现有的数据，这项研究将提供有关分子的关键信息自闭症谱系障碍 (ASD) 中小脑和细胞的多样性可用于阐明分子机制基础 ASD 神经病理学。