Diversity Supplement Grant: Effect of Short Chain Fatty Acids on Immune Dysregulation and GI Dysfunction in Autism

多样性补充补助金：短链脂肪酸对自闭症免疫失调和胃肠道功能障碍的影响

• 批准号: 10406827
• 负责人: Paul Ashwood
• 金额: $ 7.46万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406827
• 关键词: Address; Adoptive Transfer; Affect; Animal Model; Antigens; Area; Autoantibodies; Bacteria; Behavior; Behavior Disorders; Behavioral; Blood; Cell physiology; Child; Clinical; Data; Defect; Disease; Disease model; Epigenetic Process; Etiology; Exhibits; Face; Functional disorder; Grant; Immune; Immune System Diseases; Immune Targeting; Immune response; Inflammatory; Interleukin-10; Investigation; Mediator of activation protein; Modeling; Mucositis; Neurodevelopmental Disorder; Pathway interactions; Pre-Clinical Model; Production; Public Health; Regulatory T-Lymphocyte; Reporting; Research; Testing; Therapeutic; Therapeutic Intervention; Time; Transforming Growth Factors; Translating; United States; Volatile Fatty Acids; autism spectrum disorder; autistic children; behavioral impairment; behavioral phenotyping; cellular targeting; comorbidity; cytokine; epigenetic regulation; experience; experimental study; gastrointestinal; gastrointestinal epithelium; gastrointestinal symptom; immune activation; immunoregulation; improved; innovation; mouse model; novel; novel therapeutics; peripheral tolerance; pre-clinical; prevent; response; 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）在行为上定义并影响1 在美国的68名儿童中；但是，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儿童（ASD）有胃肠道（GI） 症状。在ASD中，胃肠道问题发生的频率比典型的（TD）儿童和 与更恶化的行为障碍有关。虽然对 ASD中GI问题的病理生理途径。免疫激活增加，促炎 据报道，ASD儿童和 胃肠道症状。调节性T细胞（Tregs）是维持其谱系的外围耐受性的关键介体 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 对细菌和其他腔抗原/成分的反应。我们和其他人以前已经证明 免疫抑制和TREG相关的细胞因子转化生长因子的血液水平降低 （TGF）β1和白介素（IL）-10，假定的Treg较少，并且表观遗传机制的改变较少 ASD。我们的新初步数据表明，这些免疫调节的定义更为严重 ASD和持续的GI症状。在面部和构造有效性的动物模型中，GI缺陷 观察到Treg的障碍完整性和下降。但是，尚无研究解决功能 ASD或ASD临床前模型中Treg的细胞机制。我们将测试创新的假设 Treg控制免疫反应的能力的缺陷是一种基本的病理生理机制 患有GI合并症的ASD的儿童。这是重要的投资领域 免疫控制机制的治疗靶向可能改善胃肠道屏障完整性并减轻行为 异常。将进行平行的临床和临床前实验，以研究这一假设。这 拟议的研究将确定Treg细胞功能（AIM＃1）和控制Treg的表观遗传机制 在有和没有GI符号的ASD和TD控制的两个孩子中，承诺和稳定性（AIM＃2）。 该建议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的自适应转移将用于挽救GI屏障完整性和行为 临床前小鼠模型中存在的障碍，该模型具有许多与ASD相关的特征（AIM＃3）。如果 成功，这项研究将验证ASD的变革性概念，即ASD对某些人来说是由于 免疫调节和控制中的缺陷，将验证一种新型机制之一 我们这个时代的可见公共卫生问题。