AhR activation and susceptibility to type 1 diabetes

AhR 激活和 1 型糖尿病易感性

• 批准号: 10225650
• 负责人: Allison Ehrlich
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225650
• 关键词: Address; Affect; Affinity; Anti-Inflammatory Agents; Antibiotic Therapy; Antibiotics; Antigens; Aryl Hydrocarbon Receptor; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Automobile Driving; Bacteria; Beta Cell; Birth; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cesarean section; Childhood; Data; Development; Diabetes Mellitus; Diabetes prevention; Diesel Exhaust; Diet; Disease; Disease susceptibility; Dose; Environment; Environmental Health; Environmental Risk Factor; Eragrostis; Future; Gene Expression; Goals; Health Sciences; Human; Immune; Immune response; Immune system; Immunodeficient Mouse; Immunotherapeutic agent; Inbred NOD Mice; Incidence; Indole-3-Carbinol; Institutes; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Intestines; Knockout Mice; Laboratories; Ligands; Link; Mediating; Mentors; Mission; Modeling; Monozygotic twins; Oregon; Outcome; Phase; Physiologic pulse; Physiological; Predisposition; Prevention; Prevention approach; Prevention strategy; Process; Publishing; Receptor Activation; Receptor Signaling; Regulatory T-Lymphocyte; Reporting; Research; Risk; Risk Factors; Role; Signal Transduction; Stable Populations; Structure of beta Cell of islet; Supplementation; T cell differentiation; Testing; Therapeutic; Translating; Tryptophan; Universities; Work; aryl hydrocarbon receptor ligand; base; career; cell type; cigarette smoke; clinically relevant; dietary; disorder prevention; effector T cell; efficacy evaluation; gut microbiome; gut microbiota; humanized mouse; immune function; immunopathology; immunoregulation; in vivo; insulitis; microbial; microbiome; microbiome sequencing; mouse model; non-genomic; novel strategies; particle; preclinical study; prevent; reconstitution; response; therapeutic target; transcription factor

Project Summary/Abstract Environmental factors are associated with the recent rise in type 1 diabetes (T1D), an autoimmune disease characterized by the destruction of insulin-producing beta cells. In order to develop effective T1D prevention strategies, identification of these environmental risk factors and the mechanisms by which they influence T1D immunopathogenesis is needed. Two environmental factors that have been associated with T1D susceptibility are the diet and the microbiome. One potential mechanistic link between the diet, gut microbiome and T1D is the aryl hydrocarbon receptor (AhR), a transcription factor that is activated by many environmental signals. The objective of this proposal is to determine how the interaction between the diet, microbiome, and AhR can either promote or prevent T1D development. In the first aim of this proposal (K99), Dr. Ehrlich will test the hypothesis that AhR activation by environmental ligands will induce the differentiation of CD4+ cells into either T1D- promoting Th17 cells or T1D-suppresive regulatory T cells depending upon the strength and duration of AhR activation. She will utilize non-obese diabetic (NOD) mice, a model for T1D that is sensitive to environmental perturbations, to determine how the extent of AhR activation influences CD4+ T cell function, gene expression, and T1D development under (1) physiologic conditions comparing wild type to AhR knockout mice and (2) following supplementation with increasing concentrations of the dietary AhR ligand, indole-3-carbinol. In the second aim of this proposal, Dr. Ehrlich will test two hypotheses related to the interplay between AhR, diet, microbiome, and T1D development: (1) Dietary AhR ligands modulate the abundance of intestinal bacteria that are associated with T1D development, and (2) microbiome-derived tryptophan metabolites act through the AhR to influence the autoimmune response and subsequent T1D development. Microbiome sequencing will take place during the K99 phase while the mechanistic studies, which include antibiotic treatments, fecal transfers and tryptophan supplementation, will take place during the R00 phase. In the third aim of this proposal (R00), Dr. Ehrlich will use a humanized mouse model of autoimmune insulitis to evaluate the efficacy of dietary I3C supplementation to prevent T1D immunopathology. The goal is to test the translational immunotherapeutic capabilities of dietary-derived AhR ligands for T1D prevention. The successful completion of the project will provide a missing link into the mechanism by which the diet and microbiome influence T1D. The current project will also provide the experimental basis for future studies that address other environmental AhR ligands (e.g., cigarette smoke, diesel exhaust particles) that could act as risk factors for T1D. In addition, by understanding how AhR signaling influences both proinflammatory and immunosuppressive responses, AhR ligand-based immune-mediated disease prevention strategies can be developed with greater confidence. This proposal builds upon my published and preliminary data and utilizes the strengths of my mentors, my collaborators, and unique facilities at Oregon State University to launch my independent research career in environmental health science.

项目总结/摘要 环境因素与最近1型糖尿病（T1 D）的增加有关，T1 D是一种自身免疫性疾病 以破坏产生胰岛素的β细胞为特征。为了开发有效的T1 D预防 这些环境风险因素及其影响T1 D的机制 需要免疫发病机制。与T1 D易感性相关的两个环境因素 是饮食和微生物。饮食、肠道微生物组和T1 D之间的一个潜在机制联系是 芳香烃受体（AhR），一种被许多环境信号激活的转录因子。的 该提案的目的是确定饮食，微生物组和AhR之间的相互作用如何能够 促进或预防T1 D发展。在本提案的第一个目标（K99）中，埃利希博士将检验这一假设 环境配体激活AhR将诱导CD 4+细胞分化为T1 D- 根据AhR的强度和持续时间促进Th 17细胞或T1 D抑制性调节性T细胞 activation.她将利用非肥胖糖尿病（NOD）小鼠，这是一种对环境敏感的T1 D模型。 干扰，以确定AhR活化的程度如何影响CD 4 + T细胞功能，基因表达， （1）比较野生型与AhR敲除小鼠的生理条件和（2） 在补充增加浓度的膳食AhR配体吲哚-3-甲醇之后。在 该提案的第二个目的是，埃利希博士将检验与AhR，饮食， 微生物组和T1 D发展：（1）饮食AhR配体调节肠道细菌的丰度， 与T1 D发展相关，以及（2）微生物组来源的色氨酸代谢物通过AhR起作用 影响自身免疫反应和随后的T1 D发展。微生物组测序将 在K99阶段进行，而机制研究，包括抗生素治疗、粪便转移 和色氨酸补充，将发生在R 00阶段。在本提案的第三个目标（R 00）中， 博士埃利希将使用自身免疫性胰岛炎的人源化小鼠模型来评估膳食I3 C的功效 补充以预防T1 D免疫病理学。我们的目标是测试翻译免疫系统 饮食来源的AhR配体预防T1 D的能力。该项目的顺利完成将 为饮食和微生物组影响T1 D的机制提供了一个缺失的环节。当前项目 也将为未来研究其他环境AhR配体（例如， 香烟烟雾，柴油机尾气颗粒），可能作为T1 D的危险因素。此外，通过了解 AhR信号如何影响促炎和免疫抑制反应，基于AhR配体的 免疫介导的疾病预防策略可以更有信心地发展。这一建议建立 根据我发表的和初步的数据，并利用我的导师，我的合作者和独特的优势， 在俄勒冈州州立大学的设施，开始我在环境健康科学的独立研究生涯。