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

基本信息

批准号：
10495227
负责人：
Samuel Isaac Blum
金额：
$ 1.85万
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：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10495227
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

项目摘要

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.

项目概要 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 产生促炎细胞因子/趋化因子而造成破坏细胞、巨噬细胞和其他免疫细胞最近的证据表明柯萨奇病毒。 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 T1D 的发展相关。 CVB 感染加速 T1D 的发展，部分原因是 MDA5 上调。 MDA5 在 T1D 中的作用，我们生成了一种新型 NOD 小鼠模型，称为 NOD.Ifih1ΔHel1。 NOD.Ifih1ΔHel1 小鼠的 Ifih1 解旋酶 1 结构域含有突变，该基因编码 MDA5. 表达 Ifih1ΔHel1 突变的小鼠表现出 T1D 发育延迟，这是由于然而，它会减少胰腺内促炎巨噬细胞和 T 细胞的反应。目前尚不清楚 MDA5 生化功能如何改变先天性和适应性免疫细胞调节 T1D 发病我将确定 MDA5 生化功能如何影响胰岛居民。我将确定巨噬细胞 (IRM) 的反应是促进还是抑制 T1D 的发展。如果 IRM 上的 Ifih1ΔHel1 突变影响先天病原体感应和抗原呈递为了加深对 MDA5 如何调节自身免疫的理解，我将检查 WT 和 Ifih1ΔHel1 MDA5 ATP 酶活性和 dsRNA 结合的功能。增加了 MDA5 ATP 酶活性的降低可以抑制 IRM 的反应性胰岛，从而减少炎症、自身反应性 T 细胞的激活，随后，为了检验这一假设，将定义以下独立目标：(i) 确定 Ifih1ΔHel1 突变是否损害巨噬细胞病毒感应和抗原呈递。 (ii) 确定 Ifih1ΔHel1 突变是否导致 ATP 酶活性和 dsRNA 结合降低 MDA5. 从这些研究中获得的见解将加深我们对 MDA5 作用的理解。 IRM 上的 MDA5 可驱动自身免疫性 T1D 和胰腺 β 细胞破坏。