Immune regulation and autism

免疫调节与自闭症

• 批准号: 10402782
• 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/10402782
• 关键词: 3 year old; ASD patient; Address; Adult; Affect; Amygdaloid structure; Anxiety; Area; Autism Diagnosis; 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、死后脑研究和蛋白质组学研究 血浆和脑脊液已经描述了ASD患者免疫活性的增强，同时 临床和流行病学研究表明，免疫调节的情况有所增加，如 特应性和自身免疫性。这些免疫反应的激活在患有 加重了ASD患者的行为障碍。尽管最近取得了进展，但我们的知识仍有很大差距。 关于ASD的病理生理途径。我们假设有一个共同的潜在机制 不同的发现是缺乏免疫控制或调节，可导致免疫激活和 发炎。调节性T细胞(Tregs)是维持其血统的免疫耐受的关键介质 通过表观遗传调节的承诺和功能，并抑制不适当的炎症。我们和 其他研究表明，Tregs-和免疫抑制细胞因子的频率降低。 包括转化生长因子1和白介素10。我们最新的初步数据显示 这些免疫调节缺陷与更严重的行为表型有关。然而，没有研究表明 尚未解决Tregs在ASD中的功能细胞机制。我们将检验创新假说 缺乏细胞免疫调节是ASD的早期预测风险因素，并在儿童中持续存在 已经接受诊断的自闭症患者。考虑到社交障碍和焦虑 杏仁核是ASD的主要特征，与ASD的病理生理学密切相关。我们还将 解决ASD患者和匹配对照组杏仁核缺乏免疫调节的问题 发展。这是一个重要的研究领域，因为免疫控制以治疗为靶点。 机制可能改善免疫功能，解决杏仁核异常发育和缓解 行为异常。拟议的研究将确定免疫调节、Treg细胞功能和 ASD儿童中控制Tregs承诺和稳定性的表观遗传学机制(目标1) 开发(TD)控件。在两个基于人群的前瞻性队列中，我们将检查免疫调节 后来被诊断为自闭症或TD的儿童脐带血样本的机制(目标2)。这个 该提案将直接评估免疫失调的预测性和纵向措施之间的关系 以及ASD的行为异常。我们将研究杏仁核在成年期发育过程中的发育 来自ASD和TD对照的人类样本的免疫调节(目标3)。如果成功，这项研究将 验证了变革性的概念，即对某些人来说，ASD是一种由于免疫调节和 将验证一种新的机制，以解决我们时代最明显的公共卫生问题之一。 。