Modeling Histone Demethylase Function in Neurogenesis

模拟神经发生中的组蛋白去甲基化酶功能

基本信息

批准号：
10527660
负责人：
ANITA BHATTACHARYYA
金额：
$ 41.43万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10527660
关键词：
Affect Ascorbic Acid Autopsy Biological Models Brain Brain Diseases Cell Fate Control Cell physiology Cells Cerebral cortex Code Complex DNA Data Defect Development Disease Enzymes Epigenetic Process Etiology Family Foundations Gene Expression Gene Expression Profile Gene Expression Regulation Gene Mutation Genes Genetic Transcription Genomics Grant Heterogeneity Histones Human Individual Intellectual functioning disability Lead Link Location Lysine Methyl-CpG-Binding Protein 2 Methylation Modeling Modification Molecular Mutation Neurodevelopmental Deficit Neurodevelopmental Disorder Neuronal Differentiation Neurons Pathogenesis Pathogenicity Pathway interactions Phenotype Play Proteins Rare Diseases Reader Resources Rett Syndrome Role Severities Testing Variant alpha ketoglutarate autism spectrum disorder chromatin remodeling cognitive function epigenome experimental study gene environment interaction gene function genome-wide genome-wide analysis histone demethylase human embryonic stem cell human pluripotent stem cell human stem cells induced pluripotent stem cell loss of function mutant negative affect nerve stem cell nervous system disorder neurodevelopment neurogenesis neuron development transcriptome transcriptome sequencing

项目摘要

ABSTRACT Cortical development is dependent on the coordinated expression of critical genes for proper cognitive function. Alterations in expression of these key genes during development can result in complex neurological diseases. Epigenetic mechanisms dynamically regulate expression of key genes and their loss of function disrupts cortical development and contributes to brain disorders. Rare pathogenic mutations in one epigenetic factor, KDM3B, are linked to intellectual disability and autism spectrum disorders (ASD). This exploratory proposal will test the functional consequences of these KDM3B mutations on cortical development using human embryonic stem cells with mutations of KDM3B. We will investigate both cellular and molecular differences between mutant and control cells as they differentiate into neural progenitor cells and neurons. Integration of these cellular data with molecular data will reveal the direct effects of intellectual disability related mutations in KDM3B to neurodevelopment.

抽象的皮质发育依赖于正确认知的关键基因的协调表达功能。这些关键基因在发育过程中表达的改变可能会导致复杂的结果神经系统疾病。表观遗传机制动态调节关键基因及其表达功能丧失会扰乱皮质发育并导致大脑疾病。罕见致病性一种表观遗传因子 KDM3B 的突变与智力障碍和自闭症谱系有关障碍（ASD）。该探索性提案将测试这些 KDM3B 的功能后果使用带有 KDM3B 突变的人类胚胎干细胞研究皮质发育的突变。我们将研究突变细胞和对照细胞之间的细胞和分子差异，因为它们分化为神经祖细胞和神经元。将这些细胞数据与分子数据整合数据将揭示 KDM3B 中智力障碍相关突变对神经发育。