Pathological Mechanisms of Human Cerebellar Malformations

人类小脑畸形的病理机制

基本信息

批准号：
10456683
负责人：
Kathleen Joyce Millen
金额：
$ 81.33万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10456683
关键词：
Address Affect Affective Anatomy Animal Model Atlases Attention deficit hyperactivity disorder Automobile Driving Behavioral Biological Models Biology Birth Blood Vessels Cell Cycle Cell Proliferation Cells Cellular Assay Cerebellar Diseases Cerebellar malformation Cerebellar vermis structure Cerebellum Chick Clinical Cognition Cognitive Complement Conceptions Congenital Abnormality Counseling Dandy-Walker Syndrome Data Data Set Development Diagnosis Diagnostic Family Fetal Development Gene Expression Genes Goals Gold Head Heterogeneity Histologic Human Image Immunohistochemistry In Situ In Situ Hybridization In Vitro Intellectual functioning disability Knowledge Lateral Light Linguistics Lip structure Macaca mulatta Medial Meninges Mesenchyme Methods Microscopy Modeling Molecular Morbidity - disease rate Morphology Motor Mus Neurodevelopmental Disorder Neurons Nuclear Outcome Output Pathogenesis Pathologic Play Posterior Fossa Pregnancy Process Property RNA Sequences Regulation Reporting Research Role Sampling Schizophrenia Source Specific qualifier value Ventricular autism spectrum disorder base brain malformation cell type data standards design developmental disease experimental study human fetal cerebellar tissue human model humanized mouse imaging study improved in vivo Model insight medulloblastoma mortality motor control mouse model neurogenesis nonhuman primate novel prenatal progenitor programs sensory integration single cell analysis single-cell RNA sequencing social deficits stem cells subventricular zone transcriptome sequencing transcriptomics vascular bed

项目摘要

PROJECT SUMMARY While the cerebellum's role in motor function is well recognized, the cerebellum also plays cardinal roles in affective regulation, cognitive processing, and linguistic function (1). Indeed, there is a growing recognition that disruptions of cerebellar development cause considerable cognitive, behavioral, and social deficits (2-6). Yet, though cerebellar malformations are amongst the most commonly recognized structural brain malformation in prenatal imaging (7-10). Reliable information about their cause is sparse (11, 12). Diagnosis is based on imaging studies which are often unreliable, a problem amplified during fetal development (13, 14). In stark contrast to the wealth of knowledge gained over the decades regarding the mechanisms and genes driving cerebellar development in mice and other model organisms (15-19), we actually know very little about human cerebellar development. We recently reported multiple aspects of human cerebellar development significantly differing from mice and even rhesus macaque, a non-human primate. These discoveries challenge our current mouse-centric models of normal cerebellar development and the pathogenesis human cerebellar developmental disorders (20). This proposal seeks to advance knowledge of normal developing human cerebellum and cerebellar birth defects, leveraging 1) our unique access to normal and abnormal human fetal cerebellar tissue and 2) our extensive, specific expertise of mouse and human cerebellar development and our deep knowledge of human cerebellar malformations. Our detailed characterization of normal and abnormal cerebellar development, combined with humanized mouse models will improve our understanding of the biology of normal human cerebellar development and the pathogenesis of a clinically important human cerebellar birth defect, Dandy-Walker malformation (DWM). They will provide gold standard histological and transcriptomic datasets to assess model systems of human cerebellar development, generate the first “humanized” mouse models of human cerebellar development and finally, enable improved and sorely needed prenatal diagnostic information for families affected by cerebellar malformations.

项目摘要尽管小脑在运动功能中的作用得到充分认可，但小脑也扮演着基本的角色实际上，情感调节，认知处理和语言功能的认识越来越大（1）。小脑发育的破坏会导致可观的认知，行为和社会缺陷（2-6）。然而，尽管小脑畸形是最常见的结构性脑畸形之一产前成像（7-10）。有关其原因的可靠信息很少（11，12）。诊断是基于成像研究通常是不可靠的，这是在胎儿发育过程中扩增的问题（13，14）。在斯塔克与数十年来有关机制和基因驱动的知识的财富形成鲜明对比小脑和其他模型生物的小脑发育（15-19），我们实际上对人类知之甚少小脑开发。我们最近报告了人类小脑发育的多个方面与小鼠甚至恒河猴区分开来，这是一种非人类的灵长类动物。这些发现挑战了我们的当前正常小脑发育和发病机理的以小鼠为中心的模型人小脑发育障碍（20）。该建议旨在提高人们对正常发展的人类的了解小脑和小脑出生缺陷，利用1）我们独特地获得正常和异常人类胎儿的机会小脑组织和2）我们对小鼠和人类小脑发育的广泛专业知识以及我们的对人类小脑畸形的深刻了解。我们对正常和异常的详细表征小脑的发展，结合人源化的小鼠模型将提高我们对正常人小脑发育的生物学和临床上重要的人的发病机理小脑出生缺陷，Dandy-Walker畸形（DWM）。他们将提供黄金标准的组织学和针对人类小脑开发的评估模型系统的转录组数据集，生成第一个人类小脑发育的“人性化”小鼠模型，最后，启用改进并迫切需要受小脑畸形影响的家庭的产前诊断信息。