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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，特别是因为很少有人类特定的数据是可用于正常或异常胎儿，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。

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）

Embryology.

DOI：
10.1016/b978-0-444-63956-1.00002-3
发表时间：
2018-01-01
期刊：
Handbook of clinical neurology
影响因子：
0
作者：
Haldipur, Parthiv;Dang, Derek;Millen, Kathleen J
通讯作者：
Millen, Kathleen J

What cerebellar malformations tell us about cerebellar development.

DOI：
10.1016/j.neulet.2018.05.032
发表时间：
2019-01-01
期刊：
Neuroscience letters
影响因子：
2.5
作者：
Haldipur P;Millen KJ
通讯作者：
Millen KJ

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

DOI：
10.1007/s00401-021-02355-7
发表时间：
2021-10
期刊：
Acta neuropathologica
影响因子：
12.7
作者：
Haldipur P;Bernardo S;Aldinger KA;Sivakumar T;Millman J;Sjoboen AH;Dang D;Dubocanin D;Deng M;Timms AE;Davis BD;Plummer JT;Mankad K;Oztekin O;Manganaro L;Guimiot F;Adle-Biassette H;Russo R;Siebert JR;Kidron D;Petrilli G;Roux N;Razavi F;Glass IA;Di Gioia C;Silvestri E;Millen KJ
通讯作者：
Millen KJ

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：
10.1152/jn.00509.2021
发表时间：
2022
期刊：
Journal of neurophysiology
影响因子：
2.5
作者：
Wei,AguanD;Wakenight,Paul;Zwingman,TheresaA;Bard,AngelaM;Sahai,Nikhil;Willemsen,MarjoleinH;Schelhaas,HeleniusJ;Stegmann,AlexanderPA;Verhoeven,JudithS;deMan,StellaA;Wessels,MarjaW;Kleefstra,Tjitske;Shinde,DeepaliN;Helb
通讯作者：
Helb

Phenotypic outcomes in Mouse and Human Foxc1 dependent Dandy-Walker cerebellar malformation suggest shared mechanisms.

小鼠和人类FOXC1依赖的dandy-walker小脑畸形中的表型结局提出了共同的机制。

DOI：
10.7554/elife.20898
发表时间：
2017-01-16
期刊：
eLife
影响因子：
7.7
作者：
Haldipur P;Dang D;Aldinger KA;Janson OK;Guimiot F;Adle-Biasette H;Dobyns WB;Siebert JR;Russo R;Millen KJ
通讯作者：
Millen KJ