Pathological Mechanisms of Human Cerebellar Malformations

项目摘要 虽然小脑在运动功能中的作用是公认的，但小脑在运动中也起着重要作用。 情感调节、认知加工和语言功能（1）。事实上，人们越来越认识到， 小脑发育的中断导致相当大的认知、行为和社会缺陷（2-6）。然而， 尽管小脑畸形是最常见的脑结构畸形之一， 产前成像（7-10）。关于他们的原因可靠的信息是稀疏的（11，12）。诊断基于 成像研究往往是不可靠的，一个问题在胎儿发育过程中放大（13，14）。形成鲜明 与几十年来获得的关于机制和基因驱动的丰富知识相比， 虽然我们对小鼠和其他模式生物的小脑发育（15-19）知之甚少， 小脑发育我们最近报道了人类小脑发育的多个方面， 与小鼠甚至非人类灵长类动物恒河猴不同。这些发现挑战了我们目前 正常小脑发育的小鼠中心模型和人小脑的发病机制 发育障碍（20）。这项建议旨在促进对正常发育的人类的认识， 小脑和小脑出生缺陷，利用1）我们独特的访问正常和异常的人类胎儿 小脑组织和2）我们广泛的，具体的小鼠和人类小脑发育的专业知识和我们的 对人类小脑畸形的深入了解我们对正常和异常的详细描述 小脑发育，结合人源化小鼠模型，将提高我们的理解， 正常人小脑发育的生物学和临床上重要的人类小脑发育障碍的发病机制 小脑出生缺陷，Dandy-Walker畸形（DWM）。他们将提供黄金标准的组织学， 转录组数据集来评估人类小脑发育的模型系统， 人类小脑发育的“人源化”小鼠模型，最终使人类迫切需要的改进和发展成为可能。 产前诊断信息受小脑畸形影响的家庭。

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.