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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.

项目总结