High resolution analysis of human cerebellar neurogenesis

人类小脑神经发生的高分辨率分析

• 批准号: 10457236
• 负责人: Parthiv Haldipur
• 金额: $ 23.16万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457236
• 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; 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

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.

人类小脑的出生缺陷是常见的，知之甚少，并可导致显着的认知 和运动障碍。虽然老鼠长期以来一直是人类大脑发育的模型，但我们最近 发现了人类和哺乳动物在组织发生和发育模式上的几个显著差异。 小鼠小脑，包括存在于人类中但在小鼠小脑中不存在的干细胞区。 老鼠.我们假设这些区域有助于人体内细胞数量的总体增加， 小脑，这反过来又导致了显着增加的大小和叶状。这些差异具有显著性 人类小脑疾病的发育发病机制的影响。这项研究旨在更好地 使用组织学和转录组分析表征人小脑干细胞群体。我们将 开始进行全面的免疫组织化学分析，以确定重要的发展事件， 小脑脑室区然后，我们将描述一种新发现的 在通常研究的动物模型中不存在的细胞类型。我们将对这些基因进行严格的转录组分析， 开发人类小脑来定义这些差异的分子驱动因素。这项研究利用了我们的 大量的小脑发育的专业知识，从模式生物与独特的访问，发展 人类小脑组织