Redox Regulation of Anti-Viral Responses in Type 1 Diabetes

1 型糖尿病抗病毒反应的氧化还原调节

• 批准号: 8761904
• 负责人: HUBERT M TSE
• 金额: $ 31.97万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761904
• 关键词: Address; Adoptive Transfer; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Response; Attenuated; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biochemical; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cues; Cytolysis; Development; Diabetes prevention; Disease Progression; Double-Stranded RNA; Environment; Environmental Risk Factor; Event; Generations; Genetic; Goals; Human; Immune; Immune response; Inbred NOD Mice; Inflammatory; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Interferon Type I; Knowledge; Leukocytes; Ligands; Lymphocyte; Mediating; Methodology; Modeling; Molecular; Mus; NADPH Oxidase; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Oxidation-Reduction; Oxidative Stress; Pancreas; Patients; Production; Reactive Oxygen Species; Regulation; Research; Research Proposals; Resistance; Role; Signal Transduction; Superoxides; T cell response; T-Lymphocyte; Testing; Therapeutic; Toll-like receptors; Viral; Virus; Virus Diseases; autoreactive T cell; autoreactivity; cytokine; cytotoxic; design; diabetic; human TLR3 protein; insight; islet; macrophage; monocyte; neutrophil; novel; prevent; public health relevance; response

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease resulting in pancreatic ¿-cell destruction. It is hypothesized that viral infections can trigger T1D progression by direct lysis of ¿ -cells and/or the induction of an exacerbated pro-inflammatory milieu consisting of reactive oxygen species (ROS), cytokines, and islet- infiltrating leukocytes. We recently demonstrated the importance of NADPH oxidase (NOX)-derived ROS synthesis on autoimmune diabetes, as Non-Obese Diabetic (NOD) mice unable to generate superoxide (NOD.Ncf1m1J) were highly resistant to spontaneous T1D. The resistance was partly mediated by dampened innate immune responses, as superoxide-deficient macrophages induced diminished levels of pro- inflammatory cytokines and Type I interferons upon Toll-like receptor 3 (TLR3) stimulation. The goal of this project will mechanistically define the role of ROS synthesis on macrophage differentiation and anti-viral responses in murine macrophages and human monocytes. We hypothesize that NOX-derived ROS synthesis is necessary for efficient pro-inflammatory M1 macrophage development/differentiation and viral-induced Type 1 diabetes. To address this hypothesis, the following independent and interrelated aims will be defined. (1) Determine the effects of superoxide on M1 and M2 macrophage development and function. (2) Establish the contribution of redox-dependent signals to anti-viral responses in macrophages. (3) Define the role of superoxide synthesis on bystander activation in response to viral infections. Collectively, these studies will define the fundamental roles of NOX-derived superoxide in macrophage development/differentiation in T1D and the regulation of innate immune responses to diabetogenic viruses. The knowledge gained from these studies may influence the novel design of therapeutic strategies for T1D prevention.

描述（由申请人提供）：1 型糖尿病 (T1D) 是一种 T 细胞介导的自身免疫性疾病，导致胰腺癌 ¿ -细胞破坏。据研究，病毒感染可通过直接裂解 ¿ 来引发 T1D 进展。 -细胞和/或诱导由活性氧（ROS）、细胞因子和胰岛浸润白细胞组成的加剧的促炎环境，我们最近证明了 NADPH 氧化酶（NOX）衍生的 ROS 合成对自身免疫性糖尿病的重要性，因为无法产生超氧化物的非肥胖糖尿病 (NOD) 小鼠 (NOD.Ncf1m1J) 对自发性 T1D 具有高度抵抗力，这种抵抗力部分是由其介导的。抑制先天免疫反应，因为超氧化物缺陷型巨噬细胞在 Toll 样受体 3 (TLR3) 刺激下诱导促炎细胞因子和 I 型干扰素水平降低。该项目的目标将从机制上定义 ROS 合成对巨噬细胞分化和增殖的作用。我们发现，NOX 衍生的 ROS 合成对于有效的促炎性 M1 巨噬细胞发育/分化和病毒诱导是必需的。 1 型糖尿病。为了解决这一假设，将定义以下独立且相互关联的目标 (1) 确定超氧化物对 M1 和 M2 巨噬细胞发育和功能的影响 (2) 确定氧化还原依赖性信号对抗糖尿病的作用。 (3) 定义超氧化物合成对病毒感染的旁观者激活的作用。总的来说，这些研究将定义 NOX 衍生的超氧化物在巨噬细胞发育/分化中的基本作用。 T1D 和对致糖尿病病毒的先天免疫反应的调节从这些研究中获得的知识可能会影响 T1D 预防治疗策略的新颖设计。