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

MDA5 在病毒介导的 I 型糖尿病中的作用评估

• 批准号: 8485536
• 负责人: Jennifer P Wang
• 金额: $ 38.66万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485536
• 关键词: Adult; Animal Model; Antigen-Presenting Cells; Autoimmune Diabetes; Autoimmune Process; Beta Cell; CAR receptor; Cell Maturation; Cells; Childhood; Chronic; Chronic Disease; Coxsackie B Viruses; Coxsackie Viruses; Data; Dendritic Cells; Development; Diabetes Mellitus; Disease; Disease Progression; Double-Stranded RNA; Environmental Risk Factor; Evaluation; Family; Gene Targeting; Generations; Genes; Genetic; Goals; Heart; Human; Immunologic Receptors; Immunologics; In Vitro; Individual; Infection; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Interferons; Islet Cell; Islets of Langerhans; Knock-out; Knockout Mice; Lead; Life; Link; Mediating; Modeling; Mus; Natural Immunity; Pancreas; Play; Poly I-C; Production; Rattus; Research Design; Risk; Role; Symptoms; Transgenic Mice; Variant; Viral; Virus; Virus Diseases; Zinc Fingers; age related; cell type; genome wide association study; human disease; islet; knock-down; melanoma; mimetics; mouse model; nuclease; population based; prevent; response; viral RNA; virus development

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.

描述（申请人提供）：1型糖尿病（T1D），也称为“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 β 细胞（胰腺中产生胰岛素的细胞）受到自身免疫性破坏。许多不同的遗传因素都有助于其发展，但环境因素（例如病毒感染，包括柯萨奇病毒 B (CVB)）也可能参与其中。全基因组关联研究发现人类基因黑色素瘤分化相关基因 5 (MDA5) 的特定变体与降低 T1D 风险之间存在关联。其他基于人群的研究进一步证实了这些关联。 MDA5 是一种先天免疫受体，可在病毒感染后介导 I 型干扰素 (IFN) 的产生。我们假设某些个体在 CVB 感染后更容易患上 T1D，因为他们增强了由 MDA5 介导的 I 型 IFN 反应。该项目的目标是建立 MDA5 促进病毒诱发糖尿病发展的机制。我们将使用三种不同的方法来确定 MDA5 在病毒感染情况下如何影响胰岛功能：（1）我们将使用 CVB 诱导的糖尿病转基因和基因敲除小鼠模型来评估 MDA5 在糖尿病中的作用，（2）我们我们将评估 MDA5 在病毒诱导的糖尿病大鼠模型中的作用，并且 (3) 我们将研究 MDA5 在受到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，我们将加深对先天免疫如何影响病毒感染后的疾病进程以及如何使某些个体易患 T1D 的理解。