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

基于表型的自闭症谱系障碍治疗开发中心

基本信息

批准号：
9388791
负责人：
David G Amaral
金额：
$ 232.65万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-07 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9388791
关键词：
2 year old Adolescent Affect Age Anxiety Anxiety Disorders Autistic Disorder Behavior Therapy Behavioral Behavioral trial Biological Body Size Brain Cell Line Characteristics Child Clinical Communities Development Diagnosis Diagnostic Disabled Children Disabled Persons Electrophysiology (science)Etiology Exhibits Family Frustration Functional Magnetic Resonance Imaging Genes Genetic Genotype Goals Individual Institutes Intellectual functioning disability Intervention Intervention Trial Lead Longevity Microglia Neurobiology Oligodendroglia Patients Pharmacological Treatment Phenotype Placebos Public Health Quality of life Randomized Recruitment Activity Research Resolution Resources Seizures Sertraline Services Signal Transduction Stem cells Subgroup Symptoms System Testing Translations Treatment Efficacy Youth anxiety symptoms anxiety treatment autism spectrum disorder base brain size clinically significant cognitive function cohort common symptom comparative treatment design disability early childhood effective therapy experience gray matter improved in vitro Model induced pluripotent stem cell innovation insight loved ones multidisciplinary nerve stem cell neuroimaging novel oligodendrocyte progenitor outcome forecast phenome pill programs relating to nervous system research clinical testing therapeutic target transcriptome sequencing treatment strategy white matter

项目摘要

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.

项目概要——总体如果有一个问题能够将受自闭症谱系影响的多样化家庭群体团结起来尽管已经花费了数亿美元来治疗自闭症谱系障碍（ASD），但令人沮丧的是自闭症研究表明，可用于减少亲人残疾的治疗选择非常少。我们提议的基于表型的治疗开发中心的总体目标自闭症谱系障碍 (Autism Spectrum Disorder) 旨在寻找对患有自闭症谱系障碍 (ASD) 的儿童群体进行有效治疗的目标严格定义的表型特征已经非常清楚，其原因有很多。此外，自闭症谱系障碍的一些最令人衰弱的方面是由于严重的共病所致。考虑到广泛的临床和智力障碍。由于 ASD 的行为特征，单一治疗不太可能纠正所有这些问题。基于这样的前提：识别具有临床意义的 ASD 亚型将有助于分析该中心的具体目标包括：目标#1：对自闭症谱系障碍儿童（尤其是智力障碍儿童）进行强化临床评估，更好地表征表现出临床显着焦虑的亚组。治疗有望大大改善这些儿童的生活质量。目标#2：进行为期 16 周的随机比较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患有自闭症谱系障碍的青少年。目标#3：使用功能磁共振成像来研究治疗效果的神经预测因素、治疗诱导的标志物变化，以及目标 1 中定义的焦虑亚型的特征。目标#4：对新招募的一组人进行行为、神经影像和电生理学分析患有自闭症谱系障碍 (ASD) 且大脑相对于身体尺寸不成比例增大的儿童（2-3 1/2 岁）。这一目标的主要目标是增加我们对认知功能和大脑系统的理解。影响，导致这些儿童的预后较差，这将为更有针对性的设计提供信息。虽然没有证据表明这些儿童接受标准干预的机会较少。行为疗法，很明显，它们构成了一种自闭症谱系障碍（ASD）表型，从行为疗法中获益较少如何治疗这些儿童尚不清楚，中心努力填补这一空白。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 iPSC 系将分化为神经祖细胞、少突胶质细胞和小胶质细胞识别灰质和白质对扩大大脑发育的贡献。还将通过 RNA 测序来研究细胞系，以确定基因网络和信号机制这些研究可能为这种形式的自闭症谱系障碍的药物治疗提供额外的目标。