Pathophysiology and treatment of 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 (自闭症)和智力残疾(ID)。两大障碍是缺陷的识别 大脑中扰乱行为和认知的细胞过程，以及对 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。该项目的目标就是解决这些缺陷 使用脆性X综合征的小鼠模型，这是人类ID和ASD的主要原因。脆性X 是由X染色体上的FMR1基因沉默和编码蛋白丢失引起的 FMRP。失去FMRP的主要后果包括蛋白质调节中断 神经元合成，改变离子通道功能，改变抑制电路的发展 在大脑皮层。之前对Fmr1 KO小鼠的研究表明，操纵 敏锐地纠正基础蛋白质合成的变化还可以改善多种结构， 生化和行为缺陷。因此，一条有希望的研究路线需要理解 蛋白质合成的操作如何恢复正常的神经功能。我们在美国的研究 Fmr1KO小鼠视皮层(V1)显示L层V1神经元的超兴奋性 是一种细胞自主的表型，通过抑制异常的蛋白质合成来纠正。 这种表型可能与人类高度破坏性的感觉高反应性有关。 脆性X和其他形式的ASD，但无论如何，它是一个有用的功能性报告 蛋白质合成改变的后果。值得注意的是，这种表型发生了逆转。 迅速，在抑制蛋白质合成的60分钟内。这些数据表明致病原因 半衰期短的蛋白质，可通过抑制信使核糖核酸的翻译而迅速耗尽。在目标1中 在这个探索性项目中，我们将利用遗传途径获得L5亚群 来识别这些蛋白质。如果成功，这种方法将产生一系列小说 与脆性X的异常蛋白质合成有关的治疗靶点。在目标2中，我们将 评估我们在L5中发现的一般性，并调查这种特定致病因素的影响 清醒小鼠V1功能的机制。这些实验将产生新的功能 体内治疗效果的衡量标准，如果转化到人类身上，可能会被用作潜在的 脆性X及其相关疾病中一类特殊病理生理机制的生物标志物 精神错乱。

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.