2014 Gordon Conference/Seminar on Fragile X & Autism-Related Disorders: Advances in human therapy

描述(申请人提供)：脆性X综合征(FXS)是最常见的遗传性智力缺陷形式，也是导致自闭症的最常见的单基因原因，影响1 在5000只雄性和较少数量的雌性中。自闭症谱系障碍(ASD)发生在多达三分之二的男性和三分之一的女性FXS患者中。脆性X基因(FMR1)于1991年被克隆，自那以来，已有100多个实验室利用从生物化学到遗传学的技术来模拟生物，以阐明FMR1蛋白(FMRP)的功能。FMRP主要是一种多聚核糖体相关蛋白，调节一组高度丰富的突触蛋白的翻译。除了调节翻译外，FMRP还被发现与特定的mRNAs子集相互作用并伴随到突触。在这些突触中，FMRP是一个关键的开关，它调节局部蛋白质表达的变化，以响应神经活动，导致突触因经验而增强或减弱。已经提出了特定的信号机制来介导这一控制，包括I组代谢性谷氨酸受体。此外，关于FMRP功能丧失对树突棘动力学的影响，以及不同脑区突触传递的改变，人们已经发现了许多，并且对突触反应改变对模式生物回路功能和学习的影响的了解已经扩展到。很明显，除了FXS和自闭症谱系障碍(ASD)之间的临床重叠外，这两种疾病的分子病理学可能有很大的重叠。因此，已知的导致ASD和其他神经发育障碍(NDD)的分子缺陷可能涉及信号通路中受FMRP活性调控的其他蛋白质，可能涉及其翻译受FMRP调控的蛋白质，或者可能涉及FXS模型中被证明是异常调节的神经递质系统的缺陷。针对这种途径中的靶点的分子现在正在学术实验室和制药行业进行开发和测试，以便为FXS患者提供有效的药物治疗。预计许多这些靶向治疗将在ASD或NDD患者的亚群中有治疗重叠。这次会议将汇聚脆性X、ASD和NDD领域的顶尖科学家和临床医生，特别是那些研究ASD/NDD形式的科学家和临床医生，这些ASD/NDD的分子通路功能障碍与FXS所涉及的功能重叠。主题将包括ASD和相关疾病的遗传学的最新发展，FMRP功能及其调控，疾病在分子和遗传水平上的重叠，模型系统特征，树突棘动力学和突触可塑性研究，结果指标，以及转化为治疗试验。预计这次会议将加快板凳到床边的翻译研究的步伐，为患有FXS和ASD相关疾病的患者带来重要的有针对性的治疗。

DESCRIPTION (provided by applicant): Fragile X syndrome (FXS) is the most common form of inherited intellectual deficiency and the most frequent 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 more than a hundred labs using techniques from biochemistry through genetics to model organisms to elucidate the functions of the FMR1 protein (FMRP). FMRP is primarily a polyribosome-associated protein that regulates the translation of a set of messages highly enriched for synaptic proteins. In addition to regulating translation FMRP has been found to interact with and accompany a specific subset of mRNAs to synapses. At those synapses, FMRP is a critical switch that mediates changes in local protein expression in response to neural activity, causing synapses to strengthen or weaken in response to experience. Specific signaling mechanisms have been proposed to mediate this control, including group I metabotropic glutamate receptors. In addition, a great deal has been discovered about the effects of loss of FMRP function on dendritic spine dynamics, and altered synaptic transmission in various brain areas, and understanding has been extended to the impact of altered synaptic responses on circuit function and learning in model organisms. It has become clear that in addition to the clinical overlap between FXS and autism spectrum disorders (ASD), there is likely substantial overlap in the molecular pathology of the two disorders. As such, molecular defects known to cause ASD and other neurodevelopmental disorders (NDD) may involve other proteins in the signaling pathways that are regulated by or regulate FMRP activity, may involve proteins whose translation is regulated by FMRP, or may involve defects in neurotransmitter systems shown to be dysregulated in FXS models. Molecules aimed at targets in such pathways are now being developed and tested in academic laboratories and through the pharmaceutical industry, in order to offer effective drug therapies for patients with FXS. It is expected that many of these targeted treatments will have therapeutic overlap in subsets of individuals with ASD or NDD. This conference will bring together leading scientists and clinicians in the Fragile X, ASD, and NDD fields, particularly those working on forms of ASD/NDD with dysfunctions in molecular pathways that overlap those implicated in FXS. Topics will include the latest developments in genetics of ASDs and related diseases, FMRP function and its regulation, the overlap between the diseases at the molecular and genetic level, model system characterizations, dendritic spine dynamics and synaptic plasticity studies, outcome measures, and translation to treatment trials in humans with FXS and ASD/NDD. The conference is expected to accelerate the pace of bench-to-bedside translational research to bring important targeted treatments to individuals with FXS and ASD-related disorders.