Pathological Mechanisms of Human Cerebeller Malformations

人类小脑畸形的病理机制

基本信息

批准号：
10076489
负责人：
Kathleen Joyce Millen
金额：
$ 9.97万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10076489
关键词：
6p25 Affect Behavior Biological Models Brain Brain Diseases Candidate Disease Gene Cell Culture Techniques Cell Differentiation process Cells Cellular Assay Cerebellar Diseases Cerebellar malformation Cerebellar vermis structure Cognitive Congenital Abnormality Cytoplasmic Granules Dandy-Walker Syndrome Data Data Set Databases Defect Development Diagnosis Disease Embryo Ensure Etiology Event Expression Profiling FOXC1 gene Foundations Gene Expression Genes Genetic Transcription Golgi Apparatus High-Throughput Nucleotide Sequencing Histologic Histology Human Human Pathology Image Immunohistochemistry In Situ Intellectual functioning disability Joubert syndrome Knowledge Lead Lip structure Live Birth Manuscripts Modeling Molecular Molecular Analysis Molecular Profiling Morphology Motor Mus Mutation Neuronal Differentiation Neurons Pathogenesis Pathologic Pathology Pathway interactions Patients Population Pregnancy Publishing Purkinje Cells Resources Signal Transduction Slice Stains Testing Tissue Sample Transcript Ventricular activation-induced cytidine deaminase autism spectrum disorder cell behavior cell type cohort common treatment cresyl violet exome experimental study fetal fetal diagnosis gene discovery genetic analysis granule cell histogenesis human RNA sequencing human data human fetal cells human fetal cerebellar tissue human fetal sample human fetus tissue human pluripotent stem cell improved in utero insight knowledge base laser capture microdissection malformation motor deficit mouse model neurogenesis neuroimaging physically handicapped postnatal prenatal sensory integration transcriptome

项目摘要

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.

项目概要/摘要人类中已经描述了许多小脑畸形。大多数原因是认知，除了运动和感觉统合缺陷。令人惊讶的是，人们对它的发展基础了解甚少。这些畸形，特别是因为正常或异常胎儿的人类具体数据很少小脑发育。该提案旨在增进对人类小脑发育和使用人类胎儿样本和小鼠模型研究畸形。人类特定数据将直接测试我们的小鼠衍生假设关于这些疾病的原因的有效性，并加强了正常发育数据的基础，这将为我们正在进行的人类小脑遗传分析提供信息畸形。我们将对正常人类胎儿小脑发育进行首次深入分析 4-23 妊娠周，涵盖主要发育事件。然后我们将检查人类的病理学胎儿 Dandy-Walker 畸形是最常见的人类小脑畸形，影响约 1/3000 的活体出生。小鼠模型将与这些实验结合生成，以评估该机制的机制。发育病理学。最后，我们将生成正常人类胎儿的第一个转录组数据小脑神经元。目前公开的大脑中严重缺失这些细胞类型的特定数据资源。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小脑神经元以及 mES 和 hPSC 衍生小脑的数据集神经元发育以评估其作为模型系统的有效性。此外，数据还将与来自人类小脑畸形患者的外显子组数据，以促进这些重要和重要基因的发现未充分研究的出生缺陷。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant.

CRADD 突变导致 Caspase-2 介导的神经元凋亡减少，并导致巨脑畸形和罕见的无脑畸形变异。

DOI：
发表时间：
2016-11-03
期刊：
影响因子：
9.8
作者：
Di Donato, Nataliya;Jean, Ying Y;Maga, A Murat;Krewson, Briana D;Shupp, Alison B;Avrutsky, Maria I;Roy, Achira;Collins, Sarah;Olds, Carissa;Willert, Rebecca A;Czaja, Agnieszka M;Johnson, Rachel;Stover, Jessi A;Gottlieb, Steven;Bartholdi, Deb
通讯作者：
Bartholdi, Deb

Embryology.

胚胎学。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Haldipur, Parthiv;Dang, Derek;Millen, Kathleen J
通讯作者：
Millen, Kathleen J

Redefining the Etiologic Landscape of Cerebellar Malformations.

重新定义小脑畸形的病因学景观。

DOI：
发表时间：
2019
期刊：
影响因子：
9.8
作者：
Aldinger, Kimberly A;Timms, Andrew E;Thomson, Zachary;Mirzaa, Ghayda M;Bennett, James T;Rosenberg, Alexander B;Roco, Charles M;Hirano, Matthew;Abidi, Fatima;Haldipur, Parthiv;Cheng, Chi V;Collins, Sarah;Park, Kaylee;Zeiger, Jordan;Overmann
通讯作者：
Overmann

Evidence of disrupted rhombic lip development in the pathogenesis of Dandy-Walker malformation.

Dandy-Walker 畸形发病机制中菱形唇发育中断的证据。

DOI：
发表时间：
2021
期刊：
影响因子：
12.7
作者：
Haldipur, Parthiv;Bernardo, Silvia;Aldinger, Kimberly A;Sivakumar, Tarika;Millman, Jake;Sjoboen, Alexandria H;Dang, Derek;Dubocanin, Danilo;Deng, Mei;Timms, Andrew E;Davis, Brian D;Plummer, Jasmine T;Mankad, Kshitij;Oztekin, Ozgur;Manganaro
通讯作者：
Manganaro

Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability.

人类 KCNQ5 从头突变是癫痫和智力障碍的基础。

DOI：
发表时间：
2022-07-01
期刊：
影响因子：
2.5
作者：
Wei, Aguan D;Wakenight, Paul;Zwingman, Theresa A;Bard, Angela M;Sahai, Nikhil;Willemsen, Marjolein H;Schelhaas, Helenius J;Stegmann, Alexander P A;Verhoeven, Judith S;de Man, Stella A;Wessels, Marja W;Kleefstra, Tjitske;Shinde, Deepali N;Helb
通讯作者：
Helb