Non-coding RNA regulation of early neural development

早期神经发育的非编码RNA调控

基本信息

批准号：
9888182
负责人：
Lee A. Niswander
金额：
$ 58.5万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888182
关键词：
ATRX gene Address Animal Model Attention Biogenesis Biology Brain Brain Diseases Bruck-de Lange syndrome CRISPR/Cas technology CSPG6 gene Cell Differentiation process Cell Line Chromosome Cohesion Chromosome Deletion Chromosome Segregation Complex Congenital Abnormality Data Defect Deletion Mutation Development Developmental Process Embryo Ensure Equilibrium Exons Functional disorder Gene Mutation Genes Genetic Goals Growth Human In Vitro Instruction Knock-out Knowledge Lead Link Macrocephaly Maintenance Mediating Methyl-CpG-Binding Protein 2 MicroRNAs Microcephaly Mitosis Mitotic Modeling Molecular Multiprotein Complexes Mus Mutate Neurodegenerative Disorders Neurodevelopmental Disorder Neuroepithelial Neuronal Differentiation Neuronal Injury Neurons Patients Pattern Phenotype Plant Roots Play Polyadenylation Process Protein Isoforms Proteins RNA Regulation Rett Syndrome Role Sister Chromatid Spinal Cord Testing Transcript Untranslated RNA cell behavior cell type cohesin cohesion gene function in vivo knock-down mouse model nerve stem cell nervous system disorder neurodevelopment neuroregulation novel prevent progenitor scaffold self-renewal stem cell differentiation stem cell proliferation stem cells

项目摘要

Defects in neuroepithelial progenitor self-renewal and differentiation can result in profound neurodevelopmental disorders including devastating birth defects such as microcephaly. The long-term objective of the proposed studies is to understand how neuroepithelial progenitor cell self-renewal and differentiation are coordinated. This proposal specifically focuses on a long non-coding RNA (lncRNA) that is expressed early in mouse neuroepithelial progenitor cells and, as differentiation proceeds, the lncRNA transcript is processed to yield a microRNA that is involved in neuronal differentiation. Moreover, the lncRNA physically interacts with key microcephaly proteins but the functional relationship between the lncRNA and these proteins is unknown. The major questions addressed in three Aims are as follows. Aim 1 will test the hypothesis that the lncRNA functions - independent of the miRNA - in regulating neuroepithelial progenitor proliferation and survival. Aim 1 creates cell lines and mouse models with specific deletion mutations, including a small deletion of this locus observed in a patient with microcephaly, for functional studies. Aim 2 will explore the cellular mechanism underlying the microcephaly phenotype, preliminary data which suggests a mitotic arrest. Moreover, Aim 2 will address the hypothesis that the lncRNA functions as a scaffold to help maintain sister chromatid cohesion through its interactions with the Cohesin complex, which is also implicated in microcephaly. Aim 3 will explore the mechanism underlying the temporal-spatial difference between the lncRNA host transcript and the embedded miRNA. Our overall goal is to discover new mechanisms that coordinate neuroepithelial progenitor cell proliferation and differentiation, as well as to decipher how this unexplored lncRNA mechanistically acts to allow normal brain growth. Harnessing the potential of neuroepithelial progenitor cells holds promise for the treatment of neuronal injury and neurodegenerative diseases, and dysfunction of neuroepithelial progenitors is at the root of numerous neurological disorders. Our studies will provide mechanistic links between a novel lncRNA and known microcephaly proteins to greatly extend our knowledge of this profound brain disorder.

神经上皮祖细胞自我更新和分化的缺陷可能导致严重的神经发育障碍疾病，包括毁灭性的出生缺陷，如小头畸形。拟议的长期目标研究的目的是了解神经上皮祖细胞的自我更新和分化是如何协调的。这该提案特别关注在小鼠早期表达的长非编码RNA (lncRNA) 神经上皮祖细胞，随着分化的进行，lncRNA 转录物被加工产生参与神经元分化的 microRNA。此外，lncRNA 与关键的物理相互作用小头畸形蛋白，但 lncRNA 和这些蛋白之间的功能关系尚不清楚。这三个目标解决的主要问题如下。目标 1 将检验 lncRNA 功能的假设 - 独立于 miRNA - 调节神经上皮祖细胞增殖和存活。目标 1 创造具有特定缺失突变的细胞系和小鼠模型，包括在患有小头畸形的患者，用于功能研究。目标 2 将探索潜在的细胞机制小头畸形表型，初步数据表明有丝分裂停滞。此外，目标 2 将解决假设 lncRNA 作为支架，通过其结构帮助维持姐妹染色单体的凝聚力与粘连蛋白复合物的相互作用，这也与小头畸形有关。目标 3 将探索 lncRNA宿主转录物和嵌入的嵌入物之间时空差异的机制 miRNA。我们的总体目标是发现协调神经上皮祖细胞的新机制增殖和分化，以及破译这种未经探索的 lncRNA 的机制如何发挥作用大脑正常生长。利用神经上皮祖细胞的潜力有望实现治疗神经元损伤和神经退行性疾病的发生，而神经上皮祖细胞功能障碍是其根源多种神经系统疾病。我们的研究将提供新型 lncRNA 和已知的小头畸形蛋白极大地扩展了我们对这种严重脑部疾病的认识。