High resolution analysis of human cerebellar neurogenesis

人类小脑神经发生的高分辨率分析

基本信息

批准号：
10040126
负责人：
Parthiv Haldipur
金额：
$ 28.28万
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：
2021-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040126
关键词：
Animal Model Ataxia Automobile Driving Biological Assay Biology Birth Brain Cell Count Cell Cycle Cellular Assay Cerebellar Diseases Cerebellar malformation Cerebellum Cerebral cortex Cerebrum Characteristics Cognitive Confocal Microscopy Congenital Abnormality Data Data Set Development Diagnosis Embryo Embryonic Development Event Functional disorder Gene Expression Genes Goals Histologic Human Human Development Immunohistochemistry In Situ In Situ Hybridization Interneurons Knowledge Label Modeling Molecular Molecular Profiling Morphology Motor Mus Neurodegenerative Disorders Neurodevelopmental Disorder Neuroglia Neurons Output Pathogenesis Pattern Property Purkinje Cells Radial Resolution Sampling Specificity Structure Testing Tissues Ventricular autism spectrum disorder cell type disability histogenesis human RNA sequencing improved laser capture microdissection multiphoton microscopy neurogenesis progenitor programs single-cell RNA sequencing stem cell population stem cells subventricular zone transcriptome

项目摘要

Human birth defects of the cerebellum are common, poorly understood and can cause significant cognitive and motor disabilities. Although the mouse has long been a model for human brain development, we recently discovered several significant differences in histogenesis and developmental patterns between the human and mouse cerebellum, including the presence of stem cell zones that are present in human but absent in the mouse. We hypothesize that these zones contribute to the overall increase in cell number within the human cerebellum which in turn causes a significant increase in size and foliation. These differences have significant implications for the developmental pathogenesis of human cerebellar disorders. This study aims to better characterize human cerebellar stem cell populations using histological and transcriptome analysis. We will begin by carrying out a thorough immunohistochemical analysis to identify important developmental events in the cerebellar ventricular zone. We will then characterize the morphology and distribution of a newly identified cell type absent in commonly studied animal models. We will perform rigorous transcriptome analyses of the developing human cerebellum to define the molecular drivers of these differences. This study leverages our substantial cerebellar developmental expertise from model organisms with unique access to developing human cerebellar tissue.

小脑的人类出生缺陷很常见，理解不佳，可能会引起重大认知和运动障碍。尽管老鼠长期以来一直是人脑发育的模型，但我们最近发现了人与小鼠小脑，包括存在于人类中但不存在的干细胞区域老鼠。我们假设这些区域有助于人类内部细胞数的总体增加小脑又导致大小和叶面的显着增加。这些差异具有很大的对人小脑疾病的发育发病机理的影响。这项研究旨在更好使用组织学和转录组分析来表征人小脑干细胞群体。我们将首先进行彻底的免疫组织化学分析，以确定重要的发展事件小脑心室区域。然后，我们将表征新鉴定的形态和分布常见的动物模型中不存在细胞类型。我们将对严格的转录组分析开发人小脑以定义这些差异的分子驱动因素。这项研究利用了我们的来自模型生物的大型小脑发育专业知识，具有独特的发展人小脑组织。