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: 10264698
• 负责人: Paul Ashwood
• 金额: $ 11.49万
• 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/10264698
• 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）是行为上定义的，影响1 在68名儿童在美国，然而，很少有人知道其病因和病理生理学。 有趣的是，超过一半的自闭症谱系障碍（ASD）儿童患有共病胃肠道（GI） 症状ASD中GI问题的发生频率是典型发育（TD）儿童的6-8倍， 与更严重的行为障碍有关。虽然我们对它知之甚少， ASD中胃肠道问题的病理生理学途径。增加免疫激活，促炎 据报道，ASD儿童中细胞因子的产生和针对肠上皮的自身抗体， 胃肠道症状。调节性T细胞（Regulatory T cells，Tcells）是维持外周免疫耐受的关键介质 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/组分的反应。我们和其他人之前已经证明了 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，较少的假定THBG和表观遗传机制的改变， 自闭症我们新的初步数据显示，这些免疫调节缺陷在患有以下疾病的儿童中更为严重： ASD和持续性GI症状。在ASD的表面和结构效度的动物模型中，GI缺陷 观察到屏障完整性和TdR的降低。然而，还没有研究涉及功能性 ASD或ASD的临床前模型中的细胞机制。我们将测试创新的假设， TdR控制免疫应答能力的缺陷是TdR的潜在病理生理机制。 患有ASD的儿童患有GI合并症。这是一个重要的调查领域，因为 免疫控制机制的治疗靶点可能会改善GI屏障的完整性， 异常将进行平行的临床和临床前实验以研究该假设。的 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 承诺和稳定性（目标#2）在ASD和TD对照儿童中有和没有GI症状。 该提案将直接评估具有新疗法潜力的特定细胞机制。其中一 治疗方法，过继转移TGFAP，将用于拯救GI屏障完整性和行为， 在临床前小鼠模型中存在的损伤，其表现出许多ASD相关特征（目标#3）。如果 成功的，这项研究将验证变革的概念，ASD是，对一些人来说，一种疾病，由于 缺陷的免疫调节和控制的TTRY，并将验证一个新的机制，其中一个最 我们这个时代的公共卫生问题。