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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病因谱系障碍(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交流，限制重复的行为和兴趣，以及协会智障人士。FXS是由于FMR1表达不足所致脆性X智力低下蛋白(FMRP)编码基因。早期的过度生长神经元的数量和过多的未成熟突触接触 FXS儿童的大脑，以及Fmr1 KO小鼠模型。在一次分子水平，异常过度的蛋白质合成，伴随着改变的产物关键突触蛋白，与非典型神经和突触过度生长有关。虽然FMRP的丢失会导致蛋白质合成过多，但机制改变蛋白质合成产生不同表型的基因靶点选择性 FMRP缺乏症的发病机制尚不完全清楚。MicroRNAs(MiRNAs)很小 RNA可以选择性地靶向基因转录本在RNA中进行抑制- 诱导沉默复合体(RISC)。FXS被认为与监管不善有关 MiRNAs和miRNA介导的基因抑制超过15年，但范围广泛对于靶向转录中的改变一直缺乏了解。我们建议对RISC介导的基因打靶进行全基因组定量比较在野生型和FMRP缺乏的环境中，使用小鼠和人类神经元。在初步数据的指导下，我们将研究候选的let-7miRNA家族验证Fmr1 KO中let-7 miRNA生物发生失调的假设小鼠对促进生长的mRNAs及其下游的抑制作用行为和神经解剖学表型。多管齐下的方法机械性研究和确定基因靶点和途径的优先顺序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，目标是增强我们的了解FMRP的功能并为其提供新的分子靶点对FMRP缺乏所致表型的干预。