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：
10452012
负责人：
Mark F Bear
金额：
$ 23.26万
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/10452012
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 Genetic Translation Genotype Goals Half-Life Hippocampus (Brain)Hour Human Hyperactivity Impaired cognition Inherited Intellectual functioning disability Ion Channel Knockout Mice Lead Link Measures Messenger RNA Monitor Mus Neurons Pathogenesis Pathogenicity Pathology Pharmacology 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 base chromosome loss differential expression disease phenotype experimental study improved in vivo insight metabotropic glutamate receptor 5 mouse model new therapeutic target novel patient stratification 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.

目前尚无基于机制的疗法可用于自闭症谱系障碍（ASD）和智力残疾（ID）。两个主要障碍是识别有缺陷的大脑中破坏行为和认知的细胞过程，以及基于病理生理学的客观生物标志物，可用于患者分层和评估治疗反应。该项目的目标是解决这些缺陷使用脆弱X综合征的小鼠模型，这是人ID和ASD的主要原因。脆弱的x 是由FMR1基因在X染色体上的沉默和编码蛋白的丧失引起的 FMRP。 FMRP丢失的主要后果包括蛋白质的调节中断神经元的合成，离子通道功能改变并改变了抑制回路的发展在大脑皮层中。 FMR1 KO小鼠的先前研究表明，操纵急性正确的基础蛋白质合成的改变也可以改善各种结构生化和行为缺陷。因此，一条有希望的研究需要理解蛋白质合成的操作如何恢复正常的神经元功能。我们在 FMR1 KO小鼠的视觉皮层（V1）表明层（L）5 V1神经元的过度兴奋性是一种通过抑制异常蛋白质合成来纠正的细胞自主表型。这种表型可能与人类高度破坏性的感觉高反应性有关脆弱的X和其他形式的ASD，但无论如何都是功能的有用记者蛋白质合成改变的结果。值得注意的是，这种表型的逆转发生迅速在抑制蛋白质合成的60分钟内。这些数据暗示致病性半衰期短的蛋白质会因抑制mRNA翻译而迅速耗尽。在目标1中这个探索性项目，我们将利用遗传获得L5的亚群神经元鉴定这些蛋白质。如果成功，这种方法将产生新颖的清单特异性与脆弱X中异常蛋白质合成的治疗靶标。在AIM 2中，我们将评估我们在L5中发现的一般性，并研究该特定致病性的影响 V1功能在清醒小鼠中的机制。这些实验将产生新的功能体内治疗功效的度量，如果转化为人类，则可以用作潜力脆弱X和相关的特定病理生理机制的特定病理生理机制的生物标志物疾病。