Mechanisms of beta-cell damage during virus infection

病毒感染过程中β细胞损伤的机制

• 批准号: 9126541
• 负责人: Zachary R Shaheen
• 金额: $ 4.57万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-21 至 2018-08-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9126541
• 关键词: Antiviral Response; Attenuated; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Beta Cell; Biochemical; CCR5 gene; Cells; Cessation of life; Chemosensitization; Complex; Development; Diabetes Mellitus; Double-Stranded RNA; Encephalomyocarditis virus; Environmental Risk Factor; Event; FRAP1 gene; Genetic; Genomics; Goals; Health; Inflammation Mediators; Insulin; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-1; Interleukin-1 beta; Islets of Langerhans; Lead; Macrophage Activation; Mediating; Mediator of activation protein; MicroRNAs; Molecular Genetics; Monozygotic twins; Mouse Strains; Mus; NOS2A gene; Nitric Oxide; Pathogenesis; Pathway interactions; Population; Predisposition; Production; Receptor Activation; Receptor Signaling; Research; Research Proposals; Role; Signal Pathway; Structure of beta Cell of islet; Susceptibility Gene; T-Lymphocyte; TLR3 gene; Techniques; Testing; Virus; Virus Diseases; beta-Chemokines; cell growth regulation; cell injury; chemokine receptor; cyclooxygenase 2; macrophage; mouse model; novel; prevent; receptor; research study; response; sensor

DESCRIPTION (provided by applicant): Autoimmune diabetes is characterized by the selective destruction of the insulin secreting β-cells of the pancreas. Environmental factors, such as viral infections, have been proposed to initiate β-cell damage during autoimmune diabetes development. Encephalomyocarditis virus (EMCV) induces diabetes in susceptible strains of mice. EMCV-stimulated diabetes induction is associated with macrophage activation and the expression of inflammatory mediators interleukin-1 (IL-1β) and nitric oxide. The broad goals of this research are to identify mechanisms by which virus infections contribute to β-cell damage. The C-C chemokine receptor CCR5 has been identified as a signaling receptor activated in response to EMCV infection and is responsible for regulating expression of IL-1β, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in macrophages. While CCR5 participates in regulating macrophage activation in response to EMCV infection, non-leukocyte cell populations (including β-cells) do not express this receptor. Consistent with a lack of β-cell expression of CCR5 is the identification of two micro-RNAs that reside within type 1 diabetes susceptibility loci that are predicted to target CCR5. CCR5 has also been previously identified in Genomic Wide Association Studies (GWAS) to be in a susceptibility locus of type 1 diabetes. Therefore, this research proposal will examine CCR5 as a potential susceptibility gene to virus-induced diabetes by studying the CCR5-dependent signaling pathways required for macrophage activation, the cellular regulation of CCR5 expression by micro-RNAs, and whether CCR5 contributes to susceptibility to EMCV-induced diabetes. Aim 1 will test the hypothesis that Akt and mammalian target of rapamycin complex 1 (mTORC1), in a CCR5-dependent manner, regulate the activation of macrophages in response to EMCV infection. Mouse models lacking CCR5 will be generated to test the potential role of CCR5 in regulating mouse susceptibility to EMCV-induced diabetes. Aim 2 will test the hypothesis that micro-RNAs limit the expression of CCR5 in β-cells and thereby attenuate the expression of inflammatory mediators known to cause β-cell damage in response to EMCV infection. Experiments will determine the role of micro-RNA(s) in preventing CCR5 expression in β-cells. The potential role of CCR5 expression in β-cells as a mechanism to increase β-cell susceptibility to virus- induced death will also be examined, as aberrant CCR5 expression may lead to β-cell iNOS expression during EMCV infection and thus potentiation of virus-induced damage. This proposal will elucidate mechanisms by which CCR5 controls expression of soluble mediators known to damage β-cells, by studying mechanisms of macrophage activation in response to viral infection and how micro-RNAs may suppress β-cell expression of CCR5. These results may provide information on precipitating events associated with the induction of diabetes.

描述（由申请方提供）：自身免疫性糖尿病的特征在于选择性破坏胰腺的胰岛素分泌β细胞。环境因素，如病毒感染，已被提出在自身免疫性糖尿病发展期间引发β细胞损伤。脑心肌炎病毒（EMCV）在易感品系小鼠中诱导糖尿病。EMCV刺激的糖尿病诱导与巨噬细胞活化以及炎症介质白细胞介素-1（IL-1β）和一氧化氮的表达相关。这项研究的广泛目标是确定病毒感染导致β细胞损伤的机制。C-C趋化因子受体CCR 5被鉴定为响应于EMCV感染而活化的信号传导受体，并且负责调节巨噬细胞中IL-1β、诱导型一氧化氮合酶（iNOS）和环氧合酶-2（考克斯-2）的表达。虽然CCR 5参与调节响应于EMCV感染的巨噬细胞活化，但非白细胞细胞群体（包括β细胞）不表达该受体。与CCR 5的β细胞表达缺乏一致的是鉴定出两种微RNA，其位于预测靶向CCR 5的1型糖尿病易感性基因座内。先前在基因组广泛关联研究（GWAS）中也已鉴定CCR 5在1型糖尿病的易感性位点中。因此，本研究计划将通过研究巨噬细胞活化所需的CCR 5依赖性信号通路，micro-RNA对CCR 5表达的细胞调节，以及CCR 5是否有助于EMCV诱导的糖尿病易感性，来研究CCR 5作为病毒诱导的糖尿病的潜在易感基因。目的1将测试Akt和雷帕霉素复合物的哺乳动物靶蛋白1（mTORC 1）以CCR 5依赖的方式调节巨噬细胞响应于EMCV感染的活化的假设。将产生缺乏CCR 5的小鼠模型以测试CCR 5在调节小鼠对EMCV诱导的糖尿病的易感性中的潜在作用。目的2将检验以下假设：微小RNA限制β细胞中CCR 5的表达，从而减弱已知响应于EMCV感染引起β细胞损伤的炎症介质的表达。实验将确定micro-RNA在阻止β细胞中CCR 5表达中的作用。还将检查β细胞中CCR 5表达作为增加β细胞对病毒诱导的死亡的易感性的机制的潜在作用，因为异常CCR 5表达可能导致EMCV感染期间β细胞iNOS表达，从而增强病毒诱导的损伤。该提案将阐明CCR 5控制已知损伤β细胞的可溶性介质表达的机制，通过研究巨噬细胞活化对病毒感染的反应机制以及micro-RNA如何抑制CCR 5的β细胞表达。这些结果可能提供与诱发糖尿病相关的促发事件的信息。