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Defining post-transcriptional gene regulation in FMRP-deficiency usingmiRNA:target chimeras

使用 miRNA：目标嵌合体定义 FMRP 缺陷的转录后基因调控

基本信息

批准号：
10586591
负责人：
MOLLIE Katherine MEFFERT
金额：
$ 48.4万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586591
关键词：
Affect Behavioral Binding Proteins Biochemical Biogenesis Brain Central Nervous System Child Chimera organism Cognitive Complex Coupling Data Data Set Detection Development Diagnostic FMR1 Family Fragile X Syndrome Functional disorder Gene Expression Regulation Gene Targeting Genes Genetic Diseases Goals Growth High-Throughput Nucleotide Sequencing Human Hyperactivity Immunoprecipitation Impairment Incidence Intellectual functioning disability Intervention Investigation Knock-out Knockout Mice Knowledge Ligation Link MAP Kinase Gene MAPK3 gene Mediating Messenger RNA MicroRNAs Molecular Molecular Target Morphology Motivation Mus Neuroanatomy Neurodegenerative Disorders Neurodevelopmental Disorder Neurons Pathway interactions Patients Phenotype Post-Transcriptional Regulation Production Protein Biosynthesis Protein Deficiency Proteins RNA Binding RNA-Binding Proteins RNA-Induced Silencing Complex Repression Resistance Signal Transduction Small RNA Social Interaction Specificity Synapses Techniques Testing Time Transcript Translations Untranslated RNA Validation autism spectrum disorder behavioral phenotyping brain abnormalities cell type cognitive function crosslink excitatory neuron gene repression genetic regulatory protein genome-wide human model human stem cells in vivo induced pluripotent stem cell interest mouse model nervous system disorder neural neuronal growth posttranscriptional programs protein function protein phosphatase inhibitor-2 repetitive behavior restoration social communication

项目摘要

Fragile X Syndrome (FXS) is the most common monogenic cause of Autism spectrum disorder (ASD), a group of complex neurodevelopmental disorders characterized by core diagnostic impairments in social interactions and communication, restricted repetitive behaviors and interests, and an association with intellectual disability. FXS results from deficiency in expression of the FMR1 gene encoding Fragile X Mental Retardation Protein (FMRP). An early overgrowth of neurons and excessive immature synaptic contacts have been observed in brains of children with FXS, as well as in the Fmr1 KO mouse model. At a molecular level, aberrant excessive protein synthesis, with altered production of key synaptic proteins, is implicated in the atypical neural and synaptic overgrowth. While FMRP loss can lead to excessive protein synthesis, mechanisms altering the gene-target selectivity of protein synthesis to produce the distinct phenotypes of FMRP-deficiency are incompletely understood. MicroRNAs (miRNAS) are small RNAs which can selectively target gene transcripts for repression in the RNA- induced silencing complex (RISC). FXS has been linked to misregulation of miRNAs and miRNA-mediated gene repression for over 15 years, but broad knowledge of alterations in targeted transcripts has been lacking. We propose to carry out genome-wide quantitative comparisons of RISC-mediated gene targeting in the wildtype and FMRP-deficient setting using both mice and human neurons. Directed by preliminary data, we will investigate the candidate let-7 miRNA family to test the hypothesis that dysregulation of let-7 miRNA biogenesis in the Fmr1 KO mouse contributes to altered repression of pro-growth mRNAs and downstream behavioral and neuroanatomical phenotypes. A multipronged approach for mechanistic investigation and prioritizing gene targets and pathways from genome-wide assessments will be followed by intervention to assess the functional consequences for FXS-associated phenotypes with the goal of enhancing our understanding of FMRP function and providing new molecular targets for intervention in phenotypes resulting from deficiency of FMRP.

脆性 X 综合征 (FXS) 是自闭症最常见的单基因原因谱系障碍（ASD），一组复杂的神经发育障碍其特征是社交互动中的核心诊断障碍和沟通、限制重复行为和兴趣以及协会患有智力障碍。 FXS 是 FMR1 表达缺陷所致编码脆性 X 智力迟钝蛋白 (FMRP) 的基因。早期过度生长神经元和过度未成熟的突触接触已在 FXS 儿童的大脑以及 Fmr1 KO 小鼠模型。在一个分子水平，异常的过度蛋白质合成，以及改变的生产关键的突触蛋白，与非典型神经和突触过度生长有关。虽然 FMRP 损失可能导致蛋白质合成过多，但机制会改变蛋白质合成的基因靶标选择性产生不同的表型 FMRP 缺陷的原因尚不完全清楚。 MicroRNA (miRNAS) 很小 RNA 可以选择性地靶向基因转录物以在 RNA 中进行抑制诱导沉默复合物（RISC）。 FXS 与监管不当有关 miRNA 和 miRNA 介导的基因抑制已有 15 年以上的历史，但范围广泛一直缺乏对目标转录本改变的了解。我们建议对 RISC 介导的基因靶向进行全基因组定量比较在野生型和 FMRP 缺陷环境中使用小鼠和人类神经元。根据初步数据，我们将研究候选let-7 miRNA家族检验 Fmr1 KO 中 let-7 miRNA 生物合成失调的假设小鼠有助于改变促生长 mRNA 及其下游的抑制行为和神经解剖学表型。多管齐下的方法机制研究并优先考虑基因靶标和途径全基因组评估之后将进行干预以评估功能 FXS 相关表型的后果，目的是增强我们的了解 FMRP 功能并提供新的分子靶点 FMRP 缺陷导致的表型干预。