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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）是一组复杂的神经发育障碍以社交互动中的核心诊断障碍为特征，沟通，限制重复的行为和兴趣，以及协会有智力障碍的人FXS由FMR 1表达缺陷引起脆性X智力迟钝蛋白（FMRP）基因。早期的过度生长神经元和过度不成熟的突触接触已被观察到， FXS儿童的大脑，以及Fmr 1 KO小鼠模型。在分子水平，异常的过量蛋白质合成，关键的突触蛋白，涉及非典型神经和突触过度生长。虽然FMRP缺失可导致蛋白质合成过度，但机制改变蛋白质合成的基因靶向选择性产生不同的表型对FMRP缺陷的认识还不完全。microRNA（miRNAS）是一种小分子RNA。可以选择性靶向基因转录物以抑制RNA中的RNA- 诱导沉默复合物（RISC）。FXS被认为与监管不当有关， miRNAs和miRNAs介导的基因抑制已经超过15年，但广泛对靶向转录物中的改变缺乏了解。我们建议进行RISC介导的基因打靶的全基因组定量比较在野生型和FMRP缺陷的设置使用小鼠和人类神经元。在此基础上，我们将对候选的let-7 miRNA家族进行研究为了验证在Fmr 1 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和下游mRNA的抑制行为和神经解剖表型。多管齐下的方法，机制研究和优先考虑基因靶点和途径，全基因组评估之后将进行干预，以评估功能性 FXS相关表型的后果，目的是提高我们的了解FMRP的功能，并提供新的分子靶点，干预FMRP缺乏导致的表型。