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RNA Targets for Fragile X Mental Retardation Protein

脆性 X 智力迟钝蛋白的 RNA 靶标

基本信息

批准号：
9235006
负责人：
Alexander Serganov
金额：
$ 21.19万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-26 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9235006
关键词：
Affect Affinity Anabolism Animal Model Autistic Disorder Binding Binding Proteins Binding Sites Biochemical Bioinformatics Biological Assay Brain Categories Cell physiology Characteristics Conflict (Psychology)Data Data Set Defect Development Disease Elements FMR1 Fragile X Syndrome Genetic Genetic Translation Goals Human Human Activities Inherited Intellectual functioning disability KH Domain Knowledge Learning Left Mediating Medical Memory Mental Retardation Messenger RNA Methods Mission Molecular Mutation Nervous System Physiology Neurologic Neurons Pathogenesis Play Process Protein Biosynthesis Protein Engineering Proteins Public Health Publishing RNA RNA Binding RNA Recognition Motif RNA Sequences RNA-Binding Proteins RNA-Protein Interaction Reporting Research Personnel Ribosomes Roentgen Rays Role Specificity Structure Synapses Synaptic plasticity Syndrome Tertiary Protein Structure Testing Therapeutic Translational Repression Translations United States National Institutes of Health Untranslated RNA Variant X-Ray Crystallography base combinatorial design functional loss high reward high risk human disease impression insight long term memory mutant neurological pathology next generation sequencing novel novel strategies novel therapeutic intervention protein function research study

项目摘要

Summary mRNA-binding proteins play a pivotal role in the development and function of the nervous system and defects in the function of these proteins underlie a broad spectrum of neurological pathologies. Fragile X Mental Retardation Protein (FMRP) is a paradigm of disease-associated RNA-binding proteins because of its essential contribution to the development and activity of the brain and its central role in several human disorders that affect hundreds of thousands people. The loss of FMRP due to transcriptional silencing or protein mutations leads to Fragile X syndrome (FXS), a common familial cause of inherited intellectual disability and autism that currently lacks an efficient medical treatment. On the molecular level, the absence of functional FMRP results in exaggerated protein biosynthesis that is normally held in check by FMRP-mediated translational repression of selected mRNAs. Previous studies have reported mostly conflicting datasets of FMRP targets, and despite its vital importance, the mechanism of mRNA selection by FMRP remains unclear. This lack of definitive knowledge on the principles of FMRP-RNA recognition limits both understanding of FXS and the development of rational therapeutic approaches for its treatment. Our preliminary structural data suggest that FMRP can bind RNA in sequence-specific manner and that RNA binding of FMRP is not truly promiscuous. The objective of this proposal is to determine specific RNA targets for human FMRP and understand the molecular principles of FMRP-RNA recognition. The hypothesis is that RNA-binding domains of FMRP recognize RNA sequence- specifically and that combinations of these RNA motifs determine binding to natural RNAs. To test this hypothesis, FMRP binding sites will be identified using a novel biochemical approach and structural studies. Specific Aim 1 is devoted to identification of short RNA sequences that bind specifically to isolated KH domains of FMRP by using a novel “bottom-up” approach that combines RNA capture experiments with Next Generation Sequencing. Specific Aim 2 will characterize the molecular features of FMRP that are essential for specific RNA binding by using biochemical methods and X-ray crystallography. Specific Aim 3 will aim to develop mutant FMRP proteins with altered RNA specificity to study various FMRP functions. Together, these results will define RNA sequence elements required for interactions with FMRP, help to identify natural RNA targets of FMRP, and design mutant FMRP proteins to interrogate various FMRP functions in the animal models of FXS. The proposal is highly relevant to public health and the NIH mission since it will provide insights on the RNA recognition and the mechanism of FMRP-mediated translational inhibition, the activities associated with development of FXS, autism and other disorders. Understanding how FMRP functions will advance searches for novel therapeutic interventions against FXS and related diseases.

总结