Pathological Mechanisms of Human Cerebeller Malformations

项目总结/摘要 许多小脑畸形已被描述在人类。大多数引起认知，除了 运动和感觉统合失调令人惊讶的是，人们对人类的发展基础知之甚少。 这些畸形，特别是因为几乎没有关于正常或异常胎儿的人类特定数据 小脑发育该提案旨在促进人类小脑发育的知识， 使用人类胎儿样品和小鼠模型。人类特定的数据将直接测试 有效性，我们的工作小鼠衍生的假设有关的原因，这些疾病，并加强 正常发育数据的基础，这将为我们正在进行的人类小脑的遗传分析提供信息。 畸形我们将进行第一次深入分析正常人类胎儿小脑发育， 4-23周，涵盖主要的发展活动。然后我们将研究人类的病理学 胎儿Dandy-Walker畸形是人类最常见的小脑畸形，影响约1/3000的存活率。 出生将结合这些实验产生小鼠模型，以评估免疫抑制的机制。 发育病理学最后，我们将生成正常人胎儿的第一个转录组数据， 小脑神经元这些细胞类型特异性数据在目前公开的大脑中严重缺失。 资源我们的人类胎儿小脑神经元数据将与现有的转录组数据进行比较。 内源性小鼠发育的小脑神经元以及mES和hPSC衍生的小脑神经元的数据集。 神经元的发展，以评估其有效性作为模型系统。此外，数据还将与 人类小脑畸形患者的外显子组数据，以促进这些重要和 出生缺陷研究不足。

PROJECT SUMMARY/ABSTRACT Numerous cerebellar malformations have been described in humans. Most cause cognitive, in addition to motor and sensory integration deficits. Surprisingly little is understood regarding the developmental basis of these malformations, particularly since little human specific data is available for normal or abnormal fetal cerebellar development. This proposal seeks to advance knowledge of human cerebellar development and malformations using human fetal samples and mouse models. The human-specific data will directly test the validity of our working mouse-derived hypotheses regarding the causes these disorders and strengthen the foundation of normal developmental data which will inform our ongoing genetic analyses of human cerebellar malformations. We will conduct the first in-depth analysis of normal human fetal cerebellar development from 4-23 Gestational Weeks, covering major developmental events. We will then examine the pathology of human fetal Dandy-Walker malformation the most common human cerebellar malformation, affecting ~1/3000 live births. Mouse models will be generated in conjunction with these experiments to assess the mechanisms of the developmental pathology. Finally, we will generate the first transcriptome data for normal human fetal cerebellar neurons. These cell-type specific data are critically missing from current publicly available brain resources. Our human fetal cerebellar neuron data will be compared to transcriptome data from existing datasets of endogenous mouse developing cerebellar neurons as well as mES and hPSC-derived cerebellar neurons to development to assess their validity as model systems. Further, the data will also be integrated with exome data from human cerebellar malformation patients to facilitate gene discovery for these important and understudied birth defects.