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

• 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
• 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

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.

项目摘要 - 总体 如果有一个问题将受自闭症谱系影响的潜水员和声乐社区组成 障碍（ASD），沮丧的是，尽管已经花费了数亿美元 自闭症研究，很少有治疗选择可以减少亲人的残疾。 我们拟议的基于表型的疗法开发中心的总体目标 自闭症谱系障碍是在ASD患有ASD的儿童组中发现有效治疗的目标 严格定义的表型特征。绝对清楚的是，有很多原因和 ASD的轨迹。此外，ASD最令人衰弱的某些方面是由于严重的联合摩林 焦虑，癫痫发作和智力残疾等条件。考虑到广泛的临床和 ASD的行为特征，单一治疗不太可能纠正所有这些问题。这个建议 是基于这样的前提，即确定ASD的临床有意义的亚型将有助于分析 病因和更有效的疗法的发展。该中心的具体目标包括： 目标＃1：使用ASD儿童的增强临床评估，尤其是患有智力障碍的儿童， 更好地描述表现出具有临床意义动画的亚组。适当的诊断和有效 治疗对这些儿童的生活质量得到了巨大改良的希望。 目标＃2：进行16周的随机比较治疗试验 焦虑的行为干预 自闭症儿童 （biaca），舍曲林和ASD青年的药丸安慰剂。 目标＃3：使用fMRI研究治疗效率的神经预测因子，治疗诱导的标志物 AIM 1中定义的动画子类型的更改和签名。 目标＃4：进行新招募的组的行为，神经影像学和电生理分析 相对于体型，儿童（2-3 1/2岁）的ASD和大脑肿大不成比例地扩大。这 该目标的主要目标是提高我们对认知功能和大脑系统的理解 受到影响，导致这些儿童的预后较差。这将告知更具针对性的设计 行为干预。虽然没有证据表明这些孩子获得标准的机会较少 行为疗法，很明显，它们构成了ASD表型，从中受益较少 标准干预措施。如何治疗这些孩子尚不清楚，中心努力填补这一空白。 目标＃5：从AIM＃4中调查的子集中产生IPSC患者资源。 每个受试者的IPSC线将分为神经祖细胞，少突胶质细胞和 小胶质细胞以鉴定灰质和白质对大脑增大的发育贡献。细胞 线路还将通过RNA测序进行研究，以鉴定基因网络和信号传导机制 改变。这些研究可能为这种ASD形式的药物治疗提供其他靶标。