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: 10172936
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10172936
• 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（Autism spectrum disorder， ASD）是一种行为定义的疾病，影响1