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: 8024745
• 负责人: Jennifer P Wang
• 金额: $ 41.13万
• 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/8024745
• 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. PUBLIC HEALTH RELEVANCE: Coxsackie B virus (CVB) is a common virus that can cause a spectrum of human disease that ranges from mild symptoms to severe, sometimes deadly illness involving inflammation of the heart or inflammation of the pancreas. Infection with CVB has been associated with the development of type 1 diabetes. Genome-wide association studies have established a link between variants of melanoma differentiation associated gene 5 (MDA5) and type 1 diabetes. The goal of this study is to understand the mechanisms by which CVB interacts with MDA5, which recognizes viral RNA, and can predispose certain individuals towards developing type 1 diabetes.

描述(申请人提供)：1型糖尿病(T1D)，又称青少年糖尿病，是儿童最常见的慢性疾病之一。T1D的特点是自身免疫破坏胰岛分泌胰岛素的细胞--β细胞。许多不同的遗传因素促进了它的发展，但也可能涉及环境因素，如感染病毒，包括柯萨奇病毒B组(CVB)。全基因组关联研究已经发现人类基因黑色素瘤分化相关基因5(MDA5)的特定变异与降低T1D的风险有关。其他以人群为基础的研究进一步证实了这些联系。MDA5是一种先天免疫受体，在病毒感染后介导I型干扰素(干扰素)的产生。我们推测，某些人在CVB感染后更容易发生T1D，因为他们有由MDA5介导的I型干扰素反应增强。该项目的目标是建立MDA5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MDA5在病毒感染的背景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敲除小鼠模型来评估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，以及(3)我们将研究MDA5在病毒攻击的人类胰岛I型干扰素反应中的作用。通过这些研究，我们将促进我们对先天免疫如何影响病毒感染后的疾病过程以及如何使某些人易患T1D的理解。 与公共卫生相关：柯萨奇B组病毒(CVB)是一种常见病毒，可导致一系列人类疾病，从轻微症状到严重，有时是致命的疾病，涉及心脏炎症或胰腺炎症。柯萨奇病毒感染与1型糖尿病的发生有关。全基因组关联研究已经确定了黑色素瘤分化相关基因5(MDA5)的变异与1型糖尿病之间的联系。这项研究的目的是了解CVB与MDA5相互作用的机制，MDA5识别病毒RNA，并可能使某些人易患1型糖尿病。