2012 Fragile X and Autism-Related Disorders: From Basic Neuroscience to Improved

描述（由申请人提供）：脆性X综合征（FXS）是遗传性智力缺陷的最常见形式，也是自闭症最常见的可识别单基因原因，影响1/5，000的男性和较少数量的女性。自闭症谱系障碍（ASD）发生在多达2/3的男性和1/3的女性FXS。脆性X基因（FMR 1）于1991年被克隆，从那时起，一个大的领域已经发展到一百多个实验室，使用从生物化学到遗传学的技术来模拟生物体，以阐明FMR 1蛋白（FMRP）的功能。FMR 1基因同源物已在果蝇和小鼠中发现，并在两者中产生有用的无效突变模型。FMRP参与神经元特异性信使RNA的转运、定位和表达的调控。简而言之，FMRP被认为是结合并帮助将一个关键的信息子集传输到神经活动的部位（突触）。在这些突触中，FMRP是一个关键的开关，它介导局部蛋白质表达的变化以响应神经活动-实际上导致突触根据经验的需要加强或减弱。当受影响的人的FMRP减少或缺失时，突触随着经验的变化而变化的能力要小得多，学习能力也会大大降低。最近，已经提出了特定的信号传导机制来介导突触处的这种控制，通过一组特定的Gq连接的神经递质受体，包括I组mGluR（代谢型谷氨酸受体）。除了FXS和ASD之间的临床重叠之外，这两种疾病的分子病理学也有很大的重叠。已知引起ASD的分子缺陷可能涉及调节FMRP活性的信号传导途径中的蛋白质，突触翻译由FMRP调节的蛋白质，或在FXS模型中显示失调的神经递质系统中的缺陷。针对在缺乏FMRP的情况下失调的通路中的靶标的分子现在正在学术实验室和制药行业中开发和测试，以便为FXS患者提供针对潜在神经病理学的有效药物疗法。预期许多这样的治疗将在患有ASD的个体的子集中具有治疗重叠。本次会议将汇集脆性X和ASD领域的领先科学家和临床医生，特别是那些研究ASD形式的人，这些ASD形式的分子途径与FXS中涉及的分子途径重叠。主题将包括分子通路，突触信号传导和功能，模型系统中的靶向治疗，结果测量，以及在FXS患者中转化为小分子治疗试验。该会议预计将加快从实验室到床边的转化研究的步伐，为FXS和自闭症患者带来重要的靶向治疗。 公共卫生相关性：脆性X综合征（FXS）是最常见的单基因智力残疾和自闭症谱系障碍（ASD）的原因。自FMR 1（脆性X基因）发现以来的过去20年里，在理解FXS中神经功能障碍的机制方面取得了巨大进展，现在很清楚这些机制与ASD子集中活跃的机制重叠。本次会议将汇集FXS和ASD领域的基础科学家和临床研究人员，旨在加速将新的神经科学和分子发现转化为针对FXS和ASD潜在疾病的治疗方法。

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited intellectual deficiency and the most common identifiable single gene cause of autism, affecting 1 in 5,000 males and a lesser number of females. Autism spectrum disorders (ASD) occur in up to 2/3 of males and 1/3 of females with FXS. The Fragile X gene (FMR1) was cloned in 1991 and since then a large field has grown with over one hundred labs using techniques from biochemistry through genetics to model organisms to elucidate the functions of the FMR1 protein (FMRP). FMR1 gene homologs have been found in Drosophila and mice, and useful null mutant models generated in both. FMRP has been found to be involved in the regulation of specific messenger RNA transport, localization and expression in neurons. Briefly put, FMRP is thought to bind and help transport a crucial subset of messages to the sites of neural action (the synapses). At those synapses, FMRP is a critical switch that mediates changes in local protein expression in response to neural activity - in effect causing the synapses to strengthen or weaken as required in response to experience. When FMRP is reduced or missing in an affected person, the synapses are much less able to change with experience and learning is greatly reduced. More recently, specific signaling mechanisms have been proposed to mediate this control at the synapse, via a specific set of Gq-linked neurotransmitter receptors, including group I mGluRs (metabotropic glutamate receptors). In addition to clinical overlap between FXS and ASD, there is substantial overlap in the molecular pathology of the two disorders. Molecular defects known to cause ASD may involve proteins in signaling pathways that regulate FMRP activity, proteins for which synaptic translation is regulated by FMRP, or defects in neurotransmitter systems shown to be dysregulated in FXS models. Molecules aimed at targets in pathways that are dysregulated in the absence of FMRP are now being developed and tested in academic laboratories and through the pharmaceutical industry, in order to offer effective drug therapies targeted to the underlying neural pathology fo patients with FXS. It is expected that many such treatments will have therapeutic overlap in subsets of individuals with ASD. This conference will bring together leading scientists and clinicians in the Fragile X and ASD fields, particularly those working on forms of ASD with lesions in molecular pathways that overlap those implicated in FXS. Topics will include molecular pathways, synaptic signaling and function, targeted treatment in model systems, outcome measures, and translation to small molecule treatment trials in humans with FXS. The conference is expected to accelerate the pace of bench-to-bedside translational research to bring important targeted treatments to individuals with FXS and autism. PUBLIC HEALTH RELEVANCE: Fragile X syndrome (FXS) is the most common known single gene cause of intellectual disability and autistic spectrum disorder (ASD). In the past 20 years since discovery of FMR1, the fragile X gene, tremendous progress has been made toward understanding mechanisms of neural dysfunction in FXS and it is now clear these mechanisms overlap with those active in a subset of ASD. This conference will together basic scientists and clinical researchers in the FXS and ASD field with a goal of accelerating translation of new neuroscience and molecular findings to treatments targeting the underlying disorder for both FXS and ASD.