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: 8922800
• 负责人: Zachary R Shaheen
• 金额: $ 4.52万
• 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/8922800
• 关键词: Antiviral Response; Attenuated; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; Beta Cell; Biochemical; CCR5 gene; Cells; Cessation of life; Chemokine (C-C Motif) Receptor 5; Chemosensitization; Complex; Development; Diabetes Mellitus; Double-Stranded RNA; Encephalomyocarditis virus; Environmental Risk Factor; Event; Genetic; Genomics; Goals; Health; Inflammation Mediators; Insulin; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-1; Islets of Langerhans; Lead; Macrophage Activation; Mediating; Mediator of activation protein; MicroRNAs; Molecular Genetics; Monozygotic twins; Mouse Strains; Mus; Nitric Oxide; Pancreas; Pathogenesis; Pathway interactions; Population; Predisposition; Production; Receptor Activation; Receptor Signaling; Research; Research Proposals; Role; Signal Pathway; Susceptibility Gene; T-Lymphocyte; TLR3 gene; Techniques; Testing; Virus; Virus Diseases; beta-Chemokines; cell growth regulation; cell injury; chemokine receptor; cyclooxygenase 2; human NOS2A protein; mTOR protein; 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（由适用提供）：自身免疫性糖尿病的特征是胰腺的胰岛素分泌β细胞的选择性破坏。已经提出了环境因素，例如病毒感染，以在自身免疫性糖尿病发育期间启动β细胞损伤。脑膜炎病毒（EMCV）在敏感的小鼠菌株中诱导糖尿病。 EMCV刺激的糖尿病诱导与巨噬细胞的激活有关，这项研究的广泛目标是确定病毒感染有助于β细胞损伤的机制。 C-C趋化因子受体CCR5已被鉴定为响应EMCV感染激活的信号受体，并负责控制IL-1β，诱导型一氧化氮合酶（Inos）和环氧酶-2（COX-2）的表达。尽管CCR5参与响应EMCV感染的控制巨噬细胞激活，但非白细胞细胞群（包括β细胞）并未表达该受体。与CCR5缺乏β细胞表达一致的是鉴定两个微RNA，这些微RNA位于1型糖尿病易感性位置内，预计将靶向CCR5。以前在基因组广泛的关联研究（GWA）中也已确定CCR5处于1型糖尿病的易感基因座。因此，该研究建议将通过研究巨噬细胞激活所需的CCR5依赖性信号传导途径，微-RNA对CCR5表达的细胞调节以及CCR5是否对EMCV诱导的糖尿病的易感性有助于CCR5的细胞调节，将CCR5视为对病毒诱导的糖尿病的潜在易感性基因。 AIM 1将以CCR5依赖性方式检验Akt和哺乳动物靶标1（MTORC1）的AKT和哺乳动物靶标，它调节巨噬细胞对EMCV感染的激活。将生成缺乏CCR5的小鼠模型，以测试CCR5在调节小鼠对EMCV诱导糖尿病的敏感性中的潜在作用。 AIM 2将检验以下假设：微RNA限制了β细胞中CCR5的表达，从而减弱已知会导致EMCV感染的炎症介质的表达。实验将确定微RNA在预防CCR5表达β细胞中的作用。 CCR5表达在β细胞中的潜在作用也将受到增加对病毒诱导死亡敏感性的机制，因为异常CCR5表达可能导致EMCV感染过程中β细胞iNOS表达，从而导致病毒诱导的损伤的潜力。该建议将通过研究响应病毒感染的巨噬细胞激活机制来控制已知损坏β细胞的固体介体的表达的机制，以及微RNA如何抑制CCR5的β细胞表达。这些结果可能会提供有关与糖尿病诱导相关的沉淀事件的信息。