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Determining the mechanism of IFIH1 disease-associated variants on beta-cell and immune responses in Type 1 diabetes

确定 1 型糖尿病中 IFIH1 疾病相关变异对 β 细胞和免疫反应的机制

基本信息

批准号：
10417267
负责人：
CLAYTON E MATHEWS
金额：
$ 116.62万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10417267
关键词：
ATP phosphohydrolase Affect Alanine Antiviral Response Autocrine Communication Autoimmune Diabetes Autoimmune Diseases Autoimmunity Beta Cell Binding Biochemical Biological Assay Cells Child Code Coxsackie B Viruses Coxsackie Viruses Coxsackievirus Infections Dendritic Cells Development Diabetes Mellitus Disease Double-Stranded RNA Enterovirus Environmental Risk Factor Event Fibrinogen Frequencies Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Transcription Genotype Glucose Goals Human IRF3 gene Immune Immune System Diseases Immune response Inbred NOD Mice Incidence Individual Infection Inflammatory Inflammatory Response Insulin Insulin-Dependent Diabetes Mellitus Interferon Type I Interferons Ligands Mediating Molecular Monozygotic twins Mus Mutation Onset of illness Organ Donor Outcome Pancreas Patients Peripheral Blood Mononuclear Cell Phenotype Play Positioning Attribute Predisposition Proteins Research Resistance Risk Role Serotyping Signal Pathway Signal Transduction Single Nucleotide Polymorphism Stress Structure Structure of beta Cell of islet Testing Threonine Tropism Variant Viral Virus Virus Diseases activating transcription factor cell injury cytokine design diabetes risk disorder prevention endoplasmic reticulum stress engineered stem cells environmental stressor genome wide association study high risk immune activation induced pluripotent stem cell inhibitor insulin dependent diabetes mellitus onset insulin secretion islet macrophage melanoma microbiota monocyte non-diabetic nonsynonymous mutation novel p65 programs protein structure response sensor small molecule

项目摘要

Project Summary/Abstract Type 1 diabetes (T1D) is a multifactorial autoimmune disease that requires genetic susceptibility as well as environmental triggers such as viral infections in triggering disease onset. One viral infection that is highly correlated with T1D is the Coxsackievirus B (CVB) serotype. Sensing of CVB is mediated by the melanoma differentiation-associated protein 5 (MDA5), a cytosolic sensor of dsRNA, which is encoded by the IFIH1 gene. Stimulation of the MDA5 signaling pathway activates the transcription factors IRF3 and NF-κB p65, which induce Type I IFNs synthesis, which through autocrine signaling initiate an antiviral transcriptional program. Single nucleotide polymorphisms (SNPs) in the IFIH1 gene such as rs1990760, which results in a non-synonymous mutation that changes alanine at position 946 to a threonine, is highly associated with increased risk for T1D. Studies in human PBMCs and mice have demonstrated that the A946T SNP results in an increased sensitivity to viral ligands and subsequently a stronger downstream IFN response. Macrophages have been shown previously to play an important role in T1D initiation, however, the response of β-cells to viral infection is also important. Our central hypothesis is that T1D-associated SNPs result in an exacerbated islet-resident macrophage immune response and β-cell inflammatory response following CVB3 infection which contributes to the initiation of autoimmunity. This will be tested using monocyte- derived macrophages and dendritic cells and induced pluripotent stem cells engineered to become human pancreatic β-cells from healthy donors and patients with T1D that are genotyped for IFIH1 SNPs that contribute to T1D susceptibility and resistance.

项目概要/摘要 1 型糖尿病 (T1D) 是一种多因素自身免疫性疾病，需要遗传易感性以及环境触发因素，例如引发疾病发作的病毒感染。一种病毒感染与 T1D 高度相关的是柯萨奇病毒 B (CVB) 血清型。 CVB 的感测为由黑色素瘤分化相关蛋白 5 (MDA5) 介导，MDA5 是 dsRNA 的胞质传感器，由 IFIH1 基因编码。刺激 MDA5 信号通路可激活转录因子 IRF3 和 NF-κB p65，诱导 I 型 IFN 合成，通过自分泌信号启动抗病毒转录程序。单核苷酸多态性 (SNP) 在 IFIH1 基因中，例如 rs1990760，这会导致非同义突变将第 946 位的丙氨酸更改为苏氨酸，与 T1D 风险增加高度相关。对人类 PBMC 和小鼠的研究表明，A946T SNP 会导致对病毒配体的敏感性以及随后更强的下游干扰素反应。巨噬细胞有之前已被证明在 T1D 起始中发挥重要作用，然而，β 细胞对 T1D 的反应病毒感染也很重要。我们的中心假设是，T1D 相关的 SNP 会导致加剧胰岛驻留巨噬细胞免疫反应和 β 细胞炎症反应 CVB3 感染有助于引发自身免疫。这将使用单核细胞进行测试衍生的巨噬细胞和树突状细胞以及诱导多能干细胞被改造为来自健康捐献者和 T1D 患者的人类胰腺 β 细胞，经过 IFIH1 基因分型有助于 T1D 易感性和耐药性的 SNP。