AhR activation and susceptibility to type 1 diabetes

AhR 激活和 1 型糖尿病易感性

• 批准号: 9432439
• 负责人: Allison Ehrlich
• 金额: $ 9.15万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9432439
• 关键词: Address; Affect; Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Antibiotics; Antigens; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Automobile Driving; Bacteria; Beta Cell; Birth; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; 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; Immunosuppressive Agents; 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; T-Lymphocyte; Testing; Therapeutic; Translating; Tryptophan; Universities; Work; aryl hydrocarbon receptor ligand; base; career; cell type; cigarette smoking; clinically relevant; disorder prevention; gut microbiome; gut microbiota; humanized mouse; immune function; immunopathology; immunoregulation; in vivo; microbial; microbiome; 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.

项目摘要/摘要 环境因素与自身免疫性疾病-1型糖尿病(T1D)最近的上升有关 以破坏产生胰岛素的β细胞为特征的。为了制定有效的T1D预防措施 战略，识别这些环境风险因素及其影响T1D的机制 需要免疫致病机制。与T1D易感性相关的两个环境因素 就是饮食和微生物群。饮食、肠道微生物群和T1D之间的一个潜在的机制联系是 芳香烃受体(AhR)，一种被许多环境信号激活的转录因子。这个 这项建议的目的是确定饮食、微生物组和AhR之间的相互作用如何 促进或阻止T1D的发展。在这个提议的第一个目标(K99)中，埃尔利希博士将检验这一假说 环境配体激活AhR将诱导CD4+细胞分化为T1D- 促进Th17细胞或抑制T1D的调节性T细胞取决于AhR的强度和持续时间 激活。她将利用非肥胖糖尿病(NOD)小鼠，这是一种对环境敏感的T1D模型 扰动，以确定AhR激活的程度如何影响CD4+T细胞功能，基因表达， 和在(1)比较野生型和AhR基因敲除小鼠的生理条件下的T1D发育和(2) 随着膳食中AhR配体吲哚-3-甲醇浓度的增加而补充。在 这项提议的第二个目的是，埃尔利希博士将检验两个假说，这些假说与AhR、饮食、 微生物组和T1D发育：(1)日粮AhR配体调节肠道细菌的丰度， 与T1D发育有关，以及(2)微生物组衍生的色氨酸代谢产物通过AhR发挥作用 以影响自身免疫反应和随后的T1D的发展。微生物组测序将需要 在K99阶段期间放置，同时进行机制研究，包括抗生素治疗、粪便转移 和色氨酸补充，将在R00阶段进行。在本提案的第三个目标(R00)中， Ehrlich博士将使用自身免疫性胰岛素炎的人源化小鼠模型来评估饮食I3C的疗效 补充以预防T1D免疫病理。我们的目标是测试翻译免疫疗法 饮食来源的AhR配体预防T1D的能力。该项目的成功完成将 提供了饮食和微生物群影响T1D的机制中缺失的一环。当前项目 还将为未来处理其他环境AhR配体的研究提供实验基础(例如， 香烟烟雾、柴油废气颗粒物)，这些都可能是T1D的危险因素。此外，通过理解 基于AhR配体的AhR信号如何影响促炎和免疫抑制反应 可以更有信心地制定免疫介导的疾病预防策略。这项建议建立了 基于我发布的初步数据，并利用我的导师、合作者和Unique的优势 在俄勒冈州立大学开始我在环境健康科学方面的独立研究生涯。