Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder

项目总结--总体 如果有一个问题将受自闭症谱系影响的多样化和直言不讳的家庭社区团结在一起 无序(ASD)，这是一种挫败感，尽管在这方面已经花费了数亿美元 自闭症研究表明，可以减少其亲人残疾的治疗选择如此之少。 我们建议的基于表型的治疗发展中心的总体目标是 自闭症谱系障碍是为患有自闭症的儿童群体寻找有效治疗的靶点 严格定义的表型特征。已经非常清楚了，有许多原因和 房间隔缺陷症的轨迹。此外，ASD的一些最令人衰弱的方面是由于严重的共病 焦虑、癫痫发作和智力残疾等情况。考虑到广泛的临床和 ASD的行为特征，不太可能一次治疗就能纠正所有这些问题。这项建议 是基于这样一个前提，即确定有临床意义的ASD亚型将有助于分析 病因和更有效的治疗方法的发展。该中心的具体目标包括： 目的1：加强对自闭症儿童，特别是智力残疾儿童的临床评估， 以更好地描述表现出临床显著焦虑的亚群。正确诊断，有效治疗 治疗有望极大地改善这些儿童的生活质量。 目的2：进行一项为期16周的随机对照治疗试验 焦虑症的行为干预 自闭症儿童 BIACA、舍曲林和安慰剂治疗青壮年ASD。 目的#3：使用功能磁共振成像研究治疗疗效的神经预测因子，治疗诱导的标志物 改变，以及目标1中定义的焦虑子类型的特征。 目的#4：对新招募的一组人进行行为、神经成像和电生理分析 患有自闭症和大脑相对于身体大小不成比例增大的儿童(2-3岁半)。这个 这个目标的主要目的是增加我们对认知功能和大脑系统的了解 会导致这些儿童预后较差。这将通知设计更有针对性的 行为干预。虽然没有证据表明这些儿童接触标准的机会较少 行为疗法，很明显，它们构成了一种ASD表型，受益较少 标准干预措施。如何治疗这些儿童尚不清楚，该中心正在努力填补这一空白。 目标5：从目标4中调查的儿童子集中生成IPSC患者资源。 每个受试者的IPSCs系将被分化为神经前体细胞、少突胶质细胞和 小胶质细胞，以确定灰质和白质对大脑发育的贡献。单元格 还将通过RNA测序来研究品系，以确定基因网络和信号机制 被更改了。这些研究可能为这种形式的ASD的药物治疗提供更多的靶点。

PROJECT SUMMARY – OVERALL If there is one issue that unites the diverse and vocal community of families affected by autism spectrum disorder (ASD), it is the frustration that despite the hundreds of millions of dollars that have been spent on autism research, there are so few treatment options available to decrease the disabilities of their loved ones. The overarching goal of our proposed Center for the Development of Phenotype-Based Treatments of Autism Spectrum Disorder is to discover targets for effective treatments in groups of children with ASD with rigorously defined phenotypic characteristics. It has become abundantly clear that there are many causes and trajectories of ASD. Moreover, some of the most debilitating aspects of ASD are due to the serious co-morbid conditions such as anxiety, seizures and intellectual disability. Considering the broad range of clinical and behavioral features of ASD, it is unlikely that a single treatment will correct all of these problems. This proposal is based on the premise that identifying clinically meaningful subtypes of ASD will facilitate the analysis of etiologies and the development of more effective therapeutics. The Specific Aims for the Center include: Aim #1: To use enhanced clinical evaluations of children with ASD, particularly those with intellectual disability, to better characterize the sub-group that exhibits clinically significant anxiety. Proper diagnosis and effective treatment holds the promise of a much-improved quality of life for these children. Aim #2: To conduct a 16-week randomized comparative treatment trial of Behavioral Intervention for Anxiety in Children with Autism (BIACA), sertraline, and pill placebo in youth with ASD. Aim #3: To use fMRI to investigate neural predictors of treatment efficacy, markers of treatment-induced change, and signatures of anxiety sub-types defined in Aim 1. Aim #4: To carry out behavioral, neuroimaging and electrophysiological analyses of a newly recruited group of children (2-3 1/2-years-old) with ASD and brains that are disproportionately enlarged relative to body size. The major goal of this aim is to increase our understanding of the cognitive functions and brain systems that are so impacted as to lead to a poorer prognosis for these children. This would inform the design of more targeted behavioral interventions. While there is no evidence that these children have less access to standard behavioral therapies, it has become clear that they constitute an ASD phenotype that benefits less from standard interventions. How to treat these children is not yet clear and the Center endeavors to fill this gap. Aim #5: To generate an iPSC patient resource from a subset of the children that are investigated in Aim #4. Lines of iPSCs for each subject will be differentiated into neural progenitor cells, oligodendrocytes and microglial cells to identify gray and white matter contributions to the development of enlarged brains. The cell lines will also be studied by RNA-sequencing to identify gene networks and signaling mechanisms that are altered. These studies may provide additional targets for pharmacological treatment of this form of ASD.