Immune regulation and autism

免疫调节与自闭症

• 批准号: 10152381
• 负责人: Paul Ashwood
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10152381
• 关键词: 3 year old; ASD patient; Address; Adult; Affect; Amygdaloid structure; Anxiety; Area; Autoimmune; Autoimmunity; Autopsy; Behavior; Behavioral; Biological Response Modifiers; Blood; Blood specimen; Brain; Cell Lineage; Cell physiology; Cell surface; Cells; Cerebrospinal Fluid; Child; Childhood; Clinical Research; Coculture Techniques; DNA Methylation; Data; Defect; Development; Diagnosis; Disease; Epigenetic Process; Exhibits; FOXP3 gene; Flow Cytometry; Frequencies; Functional disorder; Genetic Transcription; Growth; Human; Immune; Immune System Diseases; Immune Targeting; Immune Tolerance; Immune response; Immunologics; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Innate Immune Response; Interleukin-10; Interleukin-17; Investigation; Knowledge; Lead; Life; Link; Longevity; Maps; Measures; Mediating; Molecular; Neurodevelopmental Disorder; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Perinatal; Phenotype; Plasma; Play; Population; Process; Proteomics; Public Health; Quantitative Reverse Transcriptase PCR; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Risk; Risk Factors; Role; Sampling; Severities; Signal Pathway; Signal Transduction; Social Behavior; Social Interaction; Structure; Testing; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Umbilical Cord Blood; atopy; autism spectrum disorder; autistic children; behavioral impairment; behavioral outcome; behavioral phenotyping; bisulfite; cellular targeting; cohort; comorbidity; cytokine; demethylation; drug discovery; epidemiology study; epigenetic regulation; experimental study; forkhead protein; genetic signature; immune activation; immune function; immunoregulation; improved; individuals with autism spectrum disorder; innovation; insight; neurodevelopment; neuroinflammation; neuron loss; novel; population based; prospective; pyrosequencing; receptor; receptor function; social anxiety; stem; therapeutic target

Project Summary/Abstract: Many in vitro studies, post-mortem brain studies, and proteomic studies in plasma and cerebral spinal fluid have described the presence of increased immune activation in ASD, whilst clinical and epidemiological studies suggest that there is an increase in immune mediated conditions such as atopy and autoimmunity. Activation of these immune responses is more prominent in individuals with exacerbated behavioral impairments in ASD. Despite recent advances, there is a large gap in our knowledge regarding pathophysiological pathways in ASD. We hypothesize that an underlying mechanism common to this diverse array of findings is the lack of immune control or regulation that can lead to immune activation and inflammation. Regulatory T cells (Tregs) are key mediators of immune tolerance that maintain their lineage commitment and function through epigenetic regulation, and restrain inappropriate inflammation. We and others have previously demonstrated decreased frequencies of Tregs-and immunosuppressive cytokines including transforming growth factor (TGF)1 and interleukin (IL)-10.Our new preliminary data shows that these immune regulatory deficits are associated with more severe behavioral phenotypes. However, no studies have yet to address the functional cellular mechanisms of Tregs in ASD. We will test the innovative hypothesis that a lack of cellular immune regulation is an early predictive risk factor for ASD, and that it endures in children with ASD who have received a diagnosis. Considering that impairments in social interaction and anxiety are key features of ASD, the amygdala has been extensively implicated in ASD pathophysiology. We will also address the absence of immune regulation in the amygdala of individuals with ASD and matched controls over development. This is an important area of investigation since therapeutic targeting of immune control mechanisms might improve immune function, address abnormal amygdala development and alleviate behavioral abnormalities. The proposed studies will determine immune regulation, Treg cellular function and epigenetic mechanisms controlling Tregs commitment and stability (Aim #1) in children with ASD and typically developing (TD) controls. In two prospective, population based cohorts we will examine immune regulatory mechanisms in cord blood samples from children that later receive a diagnosis of ASD, or TD (Aim #2). The proposal will directly assess the relationship of predictive and longitudinal measures of immune dysregulation and behavior abnormalities in ASD. We will examine amygdala growth over development into adulthood and immune regulation in human samples from ASD and TD controls (Aim #3). If successful, this research will validate the transformative concept that ASD is, for some, a disorder due to defects in immune regulation and will validate a novel mechanism for one of the most visible public health concerns of our time. .

项目摘要/摘要：许多体外研究，验尸后脑研究和蛋白质组学研究 血浆和脑脊髓液已经描述了ASD中免疫激活增加的存在，同时 临床和流行病学研究表明，免疫介导的条件有所增加，例如 atopy和自身免疫。这些免疫调查的激活在患有 ASD的行为障碍加剧。尽管最近进步，我们的知识却存在很大的差距 ASD中有关的病理生理途径。我们假设这是一个共同的基本机制 各种各样的发现是缺乏免疫控制或调节，可能导致免疫激活和 炎。调节性T细胞（Tregs）是免疫耐受性的关键介体，可维持其谱系 通过表观遗传调节的承诺和功能，并抑制不当注射。我们和 其他人先前已经证明了Tregs和免疫抑制细胞因子的频率下降 包括转换生长因子（TGF）1和白介素（IL）-10。我们的新初步数据表明 这些免疫调节定义与更严重的行为表型有关。但是，没有研究 尚未解决ASD中Tregs的功能性细胞机制。我们将检验创新的假设 缺乏细胞免疫调节是ASD的早期预测危险因素，并且它在儿童中持久 与已诊断的ASD一起。考虑到社交互动和动画的损害是 ASD的主要特征，杏仁核已广泛与ASD病理生理学有关。我们也会 解决具有ASD和匹配对照的个体的杏仁核中没有免疫调节的问题 发展。自从治疗靶向免疫控制以来，这是一个重要的投资领域 机制可能会改善免疫功能，解决异常的杏仁核发展并减轻 行为异常。拟议的研究将确定免疫调节，Treg细胞功能和 控制Treg的承诺和稳定性的表观遗传机制（AIM＃1） 开发（TD）控件。在两个前瞻性，基于人群的队列中，我们将检查免疫调节性 儿童脐带血样本的机制后来接受了ASD或TD的诊断（AIM＃2）。 提案将直接评估免疫失调的预测性和纵向测量的关系 和ASD的行为异常。我们将研究杏仁核对成年期发展的增长，并 来自ASD和TD控制的人类样品中的免疫调节（AIM＃3）。如果成功，这项研究将 验证ASD是由于免疫调节和 将验证当时最明显的公共卫生问题之一的新型机制。 。