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

描述（由申请人提供）：1型糖尿病（T1D），也称为“青少年糖尿病”，是儿童最常见的慢性疾病之一。T1D的特征在于β细胞（胰腺的胰岛素产生细胞）的自身免疫性破坏。许多不同的遗传因素有助于其发展，但环境因素，如病毒感染，包括柯萨奇病毒B（CVB），也可能涉及。全基因组关联研究发现了人类基因黑色素瘤分化相关基因5（MDA5）的特定变体与T1D风险降低的关联。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，介导病毒感染后I型干扰素（IFN）的产生。我们假设某些个体在CVB感染后更容易发展为T1D，因为它们具有由MDA 5介导的增强的I型IFN应答。该项目的目标是建立MDA 5促进病毒诱导的糖尿病发展的机制。我们将使用三种不同的方法来确定在病毒感染的情况下MDA5如何影响胰岛功能：（1）我们将使用CVB诱导的糖尿病的转基因和敲除小鼠模型来评估MDA 5在糖尿病中的作用，（2）我们将评估MDA 5在病毒诱导的糖尿病的大鼠模型中的作用，以及（3）我们将研究MDA5在病毒攻击的人胰岛中I型IFN应答中的作用。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病程，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.