Immune regulation and gastrointestinal co-morbidity in autism spectrum disorders

自闭症谱系障碍的免疫调节和胃肠道共病

• 批准号: 10406965
• 负责人: Paul Ashwood
• 金额: $ 31.93万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406965
• 关键词: Address; Adoptive Transfer; Affect; Animal Model; Antigens; Area; Autoantibodies; Bacteria; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Blood; CTLA4 gene; Cell Lineage; Cell physiology; Cell surface; Cells; Child; Clinical; Coculture Techniques; DNA Methylation; Data; Defect; Development; Disease; Disease model; Epigenetic Process; Etiology; Exhibits; FOXP3 gene; Face; Flow Cytometry; Functional disorder; Generations; Genetic Transcription; IL2RA gene; Immune; Immune System Diseases; Immune Targeting; Immune Tolerance; Immune response; Immunologics; Impairment; Inflammation; Inflammatory; Interleukin-10; Interleukin-17; Interleukin-6; Intestines; Investigation; Knowledge; Lead; Link; Mediator of activation protein; Modeling; Mucositis; Mucous Membrane; Mus; Neurodevelopmental Disorder; Pathologic; Pathology; Pathway interactions; Pre-Clinical Model; Production; Public Health; Quantitative Reverse Transcriptase PCR; Regulatory T-Lymphocyte; Reporting; Research; Testing; Therapeutic; Therapeutic Intervention; Time; Transforming Growth Factors; Translating; United States; autism spectrum disorder; autistic children; behavioral impairment; behavioral phenotyping; bisulfite; cellular targeting; comorbidity; cytokine; demethylation; epigenetic regulation; experience; experimental study; forkhead protein; gastrointestinal; gastrointestinal epithelium; gastrointestinal symptom; genetic signature; immune activation; immunoregulation; improved; innovation; insight; mouse model; neurodevelopment; novel; novel therapeutics; peripheral tolerance; pre-clinical; prevent; pyrosequencing; response; stem; therapeutic target

Project Summary/Abstract: Autism spectrum disorders (ASD) are behaviorally defined and affects 1 in 68 children in the United States; however, little is known about its etiology and pathophysiology. Interestingly, over half of children with Autism Spectrum Disorders (ASD) have co-morbid gastrointestinal (GI) symptoms. GI problems occur 6-8 times more frequently in ASD than in typically developing (TD) children and are associated with more exacerbated behavioral impairments. Although Very little is known about the pathophysiological pathways underlying GI problems in ASD. Increased immune activation, pro-inflammatory cytokine production and autoantibodies directed to gut epithelium have been reported in children with ASD and GI symptoms. Regulatory T cells (Tregs) are key mediators of peripheral tolerance that maintain their lineage commitment and function through epigenetic regulation and prevent inappropriate mucosal inflammation in response to bacteria and other luminal antigens/components. We and others have previously demonstrated decreased blood levels of the immunosuppressive and Tregs-associated cytokines transforming growth factor (TGF)β1 and interleukin (IL)-10, fewer putative Tregs and alterations in epigenetic mechanisms in children with ASD. Our new preliminary data shows that these immune regulatory deficits are more severe in children with ASD and persistent GI symptoms. In animal models with face and construct validity to ASD, defects in GI barrier integrity and decreases in Tregs were observed. However, no studies have yet addressed the functional cellular mechanisms of Tregs in ASD or preclinical models of ASD. We will test the innovative hypothesis that deficits in the ability to control immune responses by Tregs are an underlying pathophysiological mechanism in children with ASD who experience GI co-morbidities. This is an important area of investigation since therapeutic targeting of immune control mechanisms might improve GI barrier integrity and alleviate behavioral abnormalities. Parallel clinical and preclinical experiments will be performed to investigate this hypothesis. The proposed studies will determine Treg cellular function (Aim #1) and epigenetic mechanisms controlling Treg commitment and stability (Aim #2) in both children with ASD and TD controls with and without GI symptoms. This proposal will directly assess specific cellular mechanisms with potential for novel therapies. One of these therapeutic approaches, adoptive transfer of Tregs, will be utilized to rescue GI barrier integrity and behavioral impairments present in a preclinical mouse model that exhibits many ASD-relevant features (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 control by Tregs, and will validate a novel mechanism for one of the most visible public health concerns of our time.

项目摘要/摘要：自闭症谱系障碍 (ASD) 从行为角度进行定义并影响 1 美国 68 名儿童；然而，对其病因和病理生理学知之甚少。 有趣的是，超过一半患有自闭症谱系障碍 (ASD) 的儿童患有胃肠道 (GI) 共病 症状。自闭症谱系障碍 (ASD) 儿童出现胃肠道问题的频率是典型发育 (TD) 儿童的 6-8 倍 与更严重的行为障碍有关。尽管人们对它知之甚少 ASD 胃肠道问题的病理生理学途径。增强免疫激活、促炎作用 据报道，患有自闭症谱系障碍 (ASD) 的儿童会产生细胞因子和针对肠上皮的自身抗体 胃肠道症状。调节性 T 细胞 (Treg) 是维持其谱系的外周耐受的关键介质 通过表观遗传调控发挥承诺和功能，并预防不适当的粘膜炎症 对细菌和其他管腔抗原/成分的反应。我们和其他人之前已经证明 免疫抑制和 Tregs 相关细胞因子转化生长因子的血液水平降低 (TGF)β1 和白细胞介素 (IL)-10、假定的 Tregs 减少以及儿童表观遗传机制的改变 自闭症谱系障碍。我们的新初步数据表明，这些免疫调节缺陷在患有以下疾病的儿童中更为严重： 自闭症谱系障碍和持续的胃肠道症状。在具有自闭症谱系障碍的面部和结构有效性的动物模型中，胃肠道缺陷 观察到屏障完整性和 Tregs 减少。然而，目前还没有研究探讨功能性 ASD 或 ASD 临床前模型中 Tregs 的细胞机制。我们将测试这个创新假设 Tregs 控制免疫反应的能力缺陷是潜在的病理生理机制 患有胃肠道合并症的自闭症谱系障碍儿童。这是一个重要的调查领域，因为 免疫控制机制的治疗目标可能会改善胃肠道屏障的完整性并减轻行为 异常。将进行并行临床和临床前实验来研究这一假设。这 拟议的研究将确定 Treg 细胞功能（目标#1）和控制 Treg 的表观遗传机制 患有自闭症谱系障碍 (ASD) 的儿童和患有或不患有胃肠道症状的 TD 对照儿童的承诺和稳定性（目标 #2）。 该提案将直接评估具有新疗法潜力的特定细胞机制。其中之一 治疗方法，Tregs 的过继转移，将被用来拯救胃肠道屏障的完整性和行为 临床前小鼠模型中存在损伤，该模型表现出许多 ASD 相关特征（目标#3）。如果 如果成功的话，这项研究将验证一个变革性的概念，即自闭症谱系障碍（ASD）对于某些人来说是一种疾病，其原因是 Tregs 的免疫调节和控制缺陷，并将验证一种新机制 我们这个时代明显的公共卫生问题。