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)是行为定义的，影响1 在美国的68名儿童中；然而，对其病因和病理生理学知之甚少。 有趣的是，超过一半的自闭症谱系障碍(ASD)儿童患有胃肠道疾病(GI) 症状。自闭症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。尽管人们对此知之甚少 ASD中胃肠道问题背后的病理生理途径。增强免疫活性，促进炎症 据报道，ASD和ASD儿童的肠道上皮细胞因子的产生和自身抗体的产生 胃肠道症状。调节性T细胞(Treg)是维持自身血统的外周耐受的关键介质 通过表观遗传调节的承诺和功能，并防止不适当的粘膜炎症 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 降低血液中免疫抑制因子和Tregs相关细胞因子的转化生长因子水平 (转化生长因子)β1和白细胞介素10，较少的潜在Tregs和表观遗传机制的变化 ASD.我们新的初步数据显示，这些免疫调节缺陷在患有 ASD和持续的胃肠道症状。在ASD的面孔和结构有效性动物模型中，GI中的缺陷 观察到屏障的完整性和Tregs的减少。然而，目前还没有研究涉及到功能 ASD或ASD临床前模型中Tregs的细胞机制。我们将检验创新假设 Tregs控制免疫反应的能力缺陷是一种潜在的病理生理机制 患有胃肠道共病的自闭症儿童。这是一个重要的调查领域，因为 免疫控制机制的治疗性靶向可能改善胃肠道屏障的完整性并缓解行为 异常现象。将进行平行的临床和临床前实验来研究这一假说。这个 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 有和没有胃肠道症状的ASD和TD对照儿童的承诺和稳定性(目标2)。 这项建议将直接评估具有新疗法潜力的特定细胞机制。这其中的一个 治疗方法，即采用Tregs移植，将用于挽救GI屏障的完整性和行为 表现出许多ASD相关特征的临床前小鼠模型中存在的损害(目标3)。如果 这项研究的成功将验证这样一个变革性的概念，即对某些人来说，ASD是一种由于 Tregs在免疫调控方面的缺陷，并将验证一种新的机制，用于 我们这个时代明显的公共卫生问题。