Role of MDA5 responses on islet-resident macrophages in Type 1 diabetes

MDA5 反应对 1 型糖尿病中胰岛驻留巨噬细胞的作用

• 批准号: 10388038
• 负责人: Samuel Isaac Blum
• 金额: $ 3.76万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388038
• 关键词: ATP phosphohydrolase; Address; Affect; American; Antigen Presentation; Antigen-Presenting Cells; Antiviral Response; Autoimmune; Autoimmune Diseases; Autoimmunity; Automobile Driving; Base Pairing; Beta Cell; Binding; Biochemical; Cells; Cellular Stress; Communities; Coxsackie Viruses; Dendritic Cells; Development; Disease; Double-Stranded RNA; Enzymes; Exhibits; Generations; Genes; Genetic Predisposition to Disease; Goals; Human; Immune; Immune system; Impairment; Inbred NOD Mice; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Interferon-alpha; Lead; Mediating; Modeling; Mus; Mutation; Non obese; Outcome; Pancreas; Patients; Pattern recognition receptor; Phagocytosis; Play; Population; Predisposition; Production; Proteins; RNA; Risk; Role; Signal Transduction; Single Nucleotide Polymorphism; Structure of beta Cell of islet; T cell response; T-Lymphocyte; Testing; Up-Regulation; Viral; Virus; Virus Replication; autocrine; autoreactive T cell; chemokine; cytokine; diabetic; diabetogenic; genome wide association study; helicase; inflammatory milieu; insight; insulin dependent diabetes mellitus onset; islet; islet autoimmunity; macrophage; melanoma; mouse model; novel; pathogen; response; sensor; targeted treatment

Project Summary Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic β-cell destruction due to the generation of proinflammatory cytokines/chemokines generated by T cells, macrophages, and other immune cells. Recent evidence has revealed that coxsackievirus group B (CVB) infection and an increase in innate viral sensor melanoma differentiation- associated protein 5 (MDA5) responses are correlated to T1D development in humans. In mice, CVB infection accelerates T1D development in part due to MDA5 upregulation. To study the role of MDA5 in T1D, we have generated a novel NOD mouse model called NOD.Ifih1ΔHel1. NOD.Ifih1ΔHel1 mice contain a mutation in the helicase 1 domain of Ifih1, the gene encoding for MDA5. Mice expressing the Ifih1ΔHel1 mutation exhibit a delay in T1D development, due to reduced proinflammatory macrophage and T cell responses within the pancreata. However, it remains unclear how MDA5 biochemical function alters innate and adaptive immune cells to regulate T1D onset. I will determine how MDA5 biochemical function affects islet-resident macrophages (IRMs) responses to either promote or dampen T1D development. I will determine if the Ifih1ΔHel1 mutation on IRMs affects innate pathogen sensing and antigen presentation to delay T1D. To enhance the understanding of how MDA5 can regulate autoimmunity, I will examine the function of WT and Ifih1ΔHel1 MDA5 ATPase activity and dsRNA binding. I hypothesize that reduced MDA5 ATPase activity can dampen IRM responsiveness within the islets, thereby reducing inflammation, activation of autoreactive T cells, and subsequently, delaying T1D onset. To test this hypothesis, the following independent aims will be defined: (i) Determine if the Ifih1ΔHel1 mutation impairs macrophage viral sensing and antigen presentation. (ii) Determine if the Ifih1ΔHel1 mutation results in reduced ATPase activity and dsRNA binding of MDA5. The insights gained from these studies will increase our understanding of the role of MDA5 on IRMs to drive autoimmune T1D and pancreatic β-cells destruction.

项目摘要 1型糖尿病（T1D）是一种自身免疫性疾病，导致胰腺β细胞 由于T 细胞，巨噬细胞和其他免疫细胞。最近的证据表明Coxsackievivirus B组（CVB）感染和先天病毒传感器黑色素瘤分化的增加 - 相关蛋白5（MDA5）反应与人类的T1D发展相关。在老鼠中， CVB感染加速了T1D的发展，部分原因是MDA5上调。研究 MDA5在T1D中的作用，我们生成了一种新型的NOD小鼠模型，称为nod.ifih1Δhel1。 NOD.IFIH1ΔHEL1小鼠在IFIH1的解旋酶1结构域中包含一个突变，该基因编码为 MDA5。表达IFIH1ΔHEL1突变的小鼠由于 胰腺内的促炎巨噬细胞和T细胞反应减少。但是，它 尚不清楚MDA5生化功能如何改变先天性和适应性免疫细胞 调节T1D发作。我将确定MDA5生化功能如何影响胰岛居民 巨噬细胞（IRMS）对促进或该死的T1D发展的反应。我会确定 如果IRMS上的IFIH1ΔHEL1突变会影响先天病原体的敏感性和抗原表现 延迟T1D。为了增强对MDA5如何调节自身免疫的理解，我将 检查WT和IFIH1ΔHEL1MDA5 ATPase活性和DSRNA结合的功能。我 假设降低的MDA5 ATPase活性可以在 胰岛，从而减少炎症，自动反应性T细胞的激活，然后 延迟T1D发作。为了检验这一假设，将定义以下独立目标：（i） 确定IFIH1ΔHEL1突变是否会损害巨噬细胞病毒敏感性和抗原表现。 （ii）确定IFIH1ΔHEL1突变是否导致ATPase活性降低和DSRNA结合 MDA5。从这些研究中获得的见解将增加我们对 IRMS上的MDA5驱动自身免疫性T1D和胰腺β细胞破坏。