Translational control in neurogenesis by ZNF804A

ZNF804A 对神经发生的翻译控制

基本信息

批准号：
10552035
负责人：
Yingwei Mao
金额：
$ 27.19万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
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：
2020-04-01 至 2025-01-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552035
关键词：
Adolescence Adult Affect Age Behavior Behavioral Binding Binding Sites Biological Assay Bipolar Disorder Brain Brain Diseases Cells DNA-Binding Proteins Defect Development Developmental Delay Disorders Developmental Gene Disease Etiology Functional disorder Genes Genetic Genetic Risk Genomics Human Immunoprecipitation Knockout Mice Knowledge Life Maps Measures Mediating Medical Mental disorders Messenger RNA Molecular Mus Neocortex Nervous System Neurons Neuropsychology Pathologic Patients Physiological Play Population Production Protein Biosynthesis Proteins Proteomics Publishing Puromycin RNA-Binding Proteins Regulation Reporting Research Proposals Risk Factors Role Schizophrenia Structure System Techniques Testing Transcript Translational Regulation Translations Variant Wild Type Mouse Zinc Fingers autism spectrum disorder crosslink crosslinking and immunoprecipitation sequencing gene interaction genetic association genetic predictors high throughput analysis in vivo innovation insight migration mosaic analysis neocortical nerve stem cell nervous system disorder neurodevelopment neurogenesis neurogranin neuroimaging neuronal circuitry novel therapeutics progenitor public health relevance risk variant stem cell proliferation theories

项目摘要

Modified Project Summary/Abstract Section Mental illnesses like schizophrenia (SZ) and bipolar disease (BP) are devastating brain disorders with global unmet medical needs. The “neurodevelopmental” theory posits that disturbances in the production and differentiation of neural progenitor cells (NPCs) cause brain development to deviate from its normal path, leading to alterations in neuronal circuitry and behavioral deficits that first manifest themselves in adolescence or adulthood. Genetic risk plays a major role in the etiology of SZ and BP and several robust and replicable risk loci have been identified with significant overlap between these two disorders. Among the top genetic associations, ZNF804A encodes a zinc finger protein. Diverse chromosomal variants of ZNF804A, including deletions and duplications, have also been found in patients with autism and developmental delay. Moreover, neuroimaging and neuropsychological studies have confirmed ZNF804A as an important genetic predictor of abnormal changes in brain structures, connectivity and behavior. However, molecular functions of ZNF804A in the nervous system are completely unknown. Thus, there is a critical need to elucidate the impacts of ZNF804A dysfunction on brain development in early life. Our central hypothesis is that ZNF804A regulates neuronal determination through interacting with translational machinery, and genetic interactions of ZNF804A with other developmental genes. The objective of this application, therefore, is to further dissect the molecular details on how ZNF804A modulates neurogenesis, and to examine genetic functional interactions between ZNF804A and its interacting genes in the knockout mice. This central hypothesis will be tested by following Specific Aims: 1) Define the mechanism of ZNF804A-mediated regulation of protein translation; 2) Determine the role of ZNF804A in neuronal fate commitment in vivo. The research proposal is innovative because this strategy combines in vivo mouse experimental systems with cutting-edge genomic/proteomic techniques. This contribution will be significant because it allows us to measure the effect of ZNF804A on the trajectory of neurodevelopment, and to identify potential underlying mechanisms contributing to developmental brain disorders.

修改的项目摘要/摘要部分精神分裂症（SZ）和躁郁症（BP）等精神疾病是具有全球未满足医疗需求的毁灭性脑部疾病。 “神经发育”理论认为，神经祖细胞（NPC）的生产和分化的困扰会导致脑发育偏离其正常路径，从而导致神经元电路的改变，而行为则定义了在青春期或成年中首先表现出来的。遗传风险在SZ和BP的病因中起主要作用，并且已经确定了这两种疾病之间的几个强大而可复制的风险基因座。在顶级遗传关联中，Znf804a编码锌指蛋白。在自闭症和发育迟缓的患者中，还发现了ZnF804A的多种染色体变体，包括缺失和重复。此外，神经影像学和神经心理学研究已证实ZNF804A是脑结构，连通性和行为异常变化的重要遗传预测指标。但是，神经系统中ZnF804a的分子功能是完全未知的。这是迫切需要阐明ZNF804A功能障碍对早期大脑发育的影响。我们的中心假设是，ZnF804A通过与翻译机制的相互作用以及Znf804a与其他发育基因的遗传相互作用来调节神经元的测定。因此，该应用的目的是进一步剖析有关ZnF804A如何调节神经发生的分子细节，并检查Znf804a及其相互作用基因之间的遗传功能相互作用。该中心假设将通过以下特定目的进行检验：1）定义Znf804a介导的蛋白质翻译调节的机理； 2）确定Znf804a在体内神经发育中的作用。研究建议具有创新性，因为该策略将体内小鼠实验系统与尖端的基因组/蛋白质组学技术相结合。这项贡献将是重要的，因为它使我们能够衡量Znf804a对神经发育轨迹的影响，并确定有助于发展脑疾病的潜在潜在基本机制。