Evaluation of the role of MDA5 in virus-mediated type I diabetes

1型糖尿病（Type 1 diabetes, T1D），又称“青少年糖尿病”，是儿童期最常见的慢性疾病之一。T1D的特点是自身免疫破坏β细胞，即胰腺的胰岛素产生细胞。许多不同的遗传因素有助于其发展，但环境因素，如感染病毒，包括柯萨奇病毒B (CVB)，也可能涉及。全基因组关联研究已经发现了人类黑色素瘤分化相关基因5 （MDA5）的特定变异与T1D风险降低之间的关联。其他基于人群的研究进一步证实了这些关联。MDA5是一种先天性免疫受体，在病毒感染后介导I型干扰素（IFN）的产生。我们假设某些个体在CVB感染后更容易发生T1D，因为他们具有由MDA5介导的I型IFN反应增强。该项目的目标是建立MDA5参与病毒诱导糖尿病发展的机制。我们将使用三种不同的方法来确定MDA5如何在病毒感染的情况下影响胰岛功能：(1)我们将使用转基因和敲除cmb诱导的糖尿病小鼠模型来评估MDA5在糖尿病中的作用，(2)我们将评估MDA5在病毒诱导的糖尿病大鼠模型中的作用，(3)我们将研究MDA5在病毒攻击的人类胰岛中I型IFN反应中的作用。通过这些研究，我们将进一步了解先天免疫如何影响病毒感染后的疾病进程，并使某些个体易患T1D。

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D), also known as "juvenile diabetes", is one of the most common chronic diseases of childhood. T1D is characterized by autoimmune destruction of beta cells, the insulin-producing cells of the pancreas. Many different genetic factors contribute to its development, but environmental factors such as infection with viruses, including coxsackievirus B (CVB), may also be involved. Genome-wide association studies have led to the discovery of an association of specific variants of the human gene melanoma differentiation-associated gene 5 (MDA5) with the decreased risk for T1D. Additional population-based studies have further confirmed these associations. MDA5 is an innate immune receptor that mediates type I interferon (IFN) production following viral infection. We hypothesize that certain individuals are more prone to develop T1D following CVB infection because they have enhanced type I IFN responses that are mediated by MDA5. The goal of this project is to establish the mechanisms by which MDA5 contributes to the development of virus- induced diabetes. We will use three distinct approaches to establish how MDA5 influences islet function in the setting of viral infection: (1) we will use a transgenic and knockout mouse model of CVB-induced diabetes to assess the role of MDA5 in diabetes, (2) we will assess the role of MDA5 in a rat model of virus-induced diabetes, and (3) we will examine the role of MDA5 in type I IFN responses in human islets challenged with virus. Through these studies, we will advance our understanding of how innate immunity influences the disease course following viral infection and can predispose certain individuals towards T1D.