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Pathophysiology and treatment of fragile X and related disorders

脆性 X 射线及相关疾病的病理生理学和治疗

基本信息

批准号：
10578794
负责人：
Mark F Bear
金额：
$ 19.39万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10578794
关键词：
Acute Address Behavior Behavioral Binding Biochemical Biological Assay Biological Markers Brain Cell physiology Cells Cerebral cortex Cerebrum Clinic Clinical Cognition Data Development Disease Electrophysiology (science)Epileptogenesis FMR1 Failure Family member Fragile X Syndrome Frequencies Functional disorder Genetic Genotype Goals Half-Life Hippocampus Hour Human Hyperactivity Impaired cognition Inherited Intellectual functioning disability Ion Channel Knockout Mice Link Measures Messenger RNA Monitor Mus Neurons Pathogenesis Pathogenicity Pathology Phenotype Process Property Protein Biosynthesis Protein Synthesis Inhibition Proteins Publishing Regulation Reporter Research Sensory Sensory Manifestations Signal Transduction Slice Stimulus Synapses Synaptic plasticity Therapeutic Therapeutic Intervention Translating Translations Treatment Efficacy V1 neuron Validation Visual Visual Cortex Work X Chromosome area striata audiogenic seizure autism spectrum disorder awake differential expression disease phenotype experimental study improved in vivo insight mRNA Translation metabotropic glutamate receptor 5 mouse model neuronal excitability new therapeutic target novel patient stratification pharmacologic potential biomarker protein protein interaction receptor response sensory cortex specific biomarkers symptomatic improvement therapy resistant treatment response

项目摘要

Currently there are no mechanism-based therapies available for autism spectrum disorders (ASDs) and intellectual disability (ID). Two major barriers are the identification of defective cellular processes within the brain that disrupt behavior and cognition, and the validation of an objective biomarker based on pathophysiology that can be used for patient stratification and assessing treatment response. The objectives of this project are to address these deficiencies using the mouse model of fragile X syndrome, a leading cause of human ID and ASD. Fragile X is caused by silencing of the FMR1 gene on the X chromosome and loss of the encoded protein FMRP. Major consequences of the loss of FMRP include disrupted regulation of protein synthesis in neurons, altered ion channel function, and altered development of inhibitory circuits in the cerebral cortex. Previous studies in the Fmr1 KO mouse showed that manipulations that acutely correct alterations in basal protein synthesis also improve a wide variety of structural, biochemical, and behavioral deficits. Thus, one promising line of research entails understanding how the manipulations of protein synthesis restore normal neuronal function. Our studies in the visual cortex (V1) of Fmr1 KO mice have shown that hyperexcitability of layer (L) 5 V1 neurons is a cell-autonomous phenotype that is corrected by suppressing aberrant protein synthesis. This phenotype may be relevant to sensory hyperresponsivity that is highly disruptive in human fragile X and other forms of ASD, but regardless it is a useful reporter of a functional consequence of altered protein synthesis. Remarkably, reversal of this phenotype occurs rapidly, within 60 minutes of suppressing protein synthesis. These data implicate pathogenic proteins with a short half-life that are rapidly depleted by inhibiting mRNA translation. In Aim 1 of this exploratory project, we will take advantage of genetic access to a subpopulation of L5 neurons to identify these proteins. If successful, this approach will yield a list of novel therapeutic targets specifically linked to aberrant protein synthesis in fragile X. In Aim 2, we will assess the generality of our findings in L5, and investigate the impact of this specific pathogenic mechanism on the function of V1 in awake mice. These experiments will yield novel functional measures of treatment efficacy in vivo that, if translated to humans, could be used as potential biomarkers of a specific class of pathophysiological mechanisms in fragile X and related disorders.

目前还没有针对自闭症谱系障碍的基于机制的治疗方法