Differential roles for type I interferon and inflammatory pathways in autoimmune diabetes

I 型干扰素和炎症通路在自身免疫性糖尿病中的不同作用

• 批准号: 10189495
• 负责人: Jennifer P Wang
• 金额: $ 59.24万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189495
• 关键词: Anti-Inflammatory Agents; Antiviral Agents; Autoimmune Diabetes; Autoimmune Diseases; Automobile Driving; Beta Cell; CASP1 gene; CRISPR/Cas technology; Candidate Disease Gene; Cells; Cytokine Signaling; Development; Diabetes Mellitus; Dose; Gene Expression; Gene Expression Profile; Genes; Goals; Human; Hyperglycemia; IFNAR1 gene; Immune; Immune response; Immune system; Incidence; Individual; Inflammasome; Inflammation; Inflammatory; Innate Immune Response; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Receptor; Interferon Type I; Interferons; Interleukin-1; Interleukin-1 Receptors; Intervention; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Kilham' s rat virus; Knock-out; Lead; Link; Lymphoid Tissue; Mediating; Modeling; Monitor; Pancreas; Pathogenesis; Pathologic; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Poly C; Poly I-C; Population; Prevention strategy; Process; Rattus; Research; Rheumatoid Arthritis; Risk; Role; Salicylic Acids; Signal Pathway; Signal Transduction; Sodium Salicylate; Spleen; Stimulus; Streptozocin; Structure of beta Cell of islet; Susceptibility Gene; Systemic Lupus Erythematosus; Testing; Time; Viral; Virus; Virus Diseases; anakinra; autoimmune pathogenesis; cytokine; design; diabetes pathogenesis; diabetic rat; disorder prevention; euglycemia; experimental study; genome editing; human disease; immune activation; innate immune mechanisms; innate immune pathways; insulitis; islet; lead candidate; lymph nodes; mimetics; prevent; receptor; receptor-mediated signaling; recruit; response; single-cell RNA sequencing; transcriptome sequencing; type I interferon receptor; virus development

Project Abstract ! Despite decades of intensive research, type 1 diabetes (T1D), which is characterized by autoimmune destruction of the insulin-producing beta cells of the pancreas, still cannot be prevented. Understanding the innate immunologic mechanisms for the development of T1D is crucial for developing preventive strategies. Dissecting the interactions between environmental stimuli such as viral infection, immune responses, and the development of insulitis (a key pathologic feature of T1D) in humans is extremely challenging. By temporally defining such interactions in the rat model of autoimmune diabetes, we believe we can develop specific interventions to target the human disease process. We have found that the type I interferon (IFN) receptor (IFNAR), a key component of the innate immune response to viral infection, is critically involved in development of virus-induced autoimmune diabetes in weanling LEW.1WR1 rats. We will further define the role of type I IFN in the development of diabetes by comparing immune cell recruitment between WT and IFNAR-/- rats and examining transcriptional profiles at the single cell level. We will also determine if intrinsic IFN signaling in islets, including beta cells, contributes to the development of T1D by performing islet transplants between WT and IFNAR-/- rats. Inflammatory pathways also participate in the pathogenesis of autoimmune diabetes. We will determine if blockade of the interleukin-1 (IL-1) receptor will prevent type I IFN-independent diabetes. We will delineate mechanisms by which the anti- inflammatory drug salicylate prevents diabetes. We plan to create a knockout rat using a CRISPR-Cas9 gene editing strategy to examine the inflammatory pathway-mediated contribution to the development of autoimmune diabetes. Through the proposed studies, we will gain a fundamental understanding of immunologic responses that lead to autoimmune diabetes. Notably, we will define both temporal aspects as well as key cell populations involved in innate immune responses. Results from these experiments will reveal specific innate immune pathways that participate in the development of insulitis and autoimmune diabetes and are essential for developing preventive strategies for individuals who are at greatest risk for T1D.

项目摘要 ！尽管经过数十年的深入研究，1 型糖尿病 (T1D) 的特点是自身免疫性 胰腺中产生胰岛素的β细胞的破坏仍然无法预防。了解 T1D 发展的先天免疫机制对于制定预防策略至关重要。 剖析环境刺激（如病毒感染、免疫反应和免疫反应）之间的相互作用 人类胰岛素炎（T1D 的一个关键病理特征）的发展极具挑战性。按时间 在自身免疫性糖尿病大鼠模型中定义这种相互作用，我们相信我们可以开发出特定的 针对人类疾病过程的干预措施。 我们发现 I 型干扰素 (IFN) 受体 (IFNAR) 是先天免疫的关键组成部分 对病毒感染的反应，与病毒诱导的自身免疫性糖尿病的发展密切相关 断奶LEW.1WR1大鼠。我们将进一步明确 I 型干扰素在糖尿病发展中的作用 比较 WT 和 IFNAR-/- 大鼠之间的免疫细胞募集并检查转录谱 单细胞水平。我们还将确定胰岛（包括 β 细胞）中的内在 IFN 信号传导是否有助于 通过在 WT 和 IFNAR-/- 大鼠之间进行胰岛移植来发展 T1D。炎症途径 也参与自身免疫性糖尿病的发病机制。我们将确定是否阻断白介素-1 (IL-1) 受体可预防 I 型 IFN 依赖性糖尿病。我们将制定机制，通过这些机制， 炎症药物水杨酸盐可预防糖尿病。我们计划使用 CRISPR-Cas9 基因创建敲除大鼠 编辑策略来检查炎症途径介导的对发展的贡献 自身免疫性糖尿病。 通过拟议的研究，我们将对免疫反应有一个基本的了解 导致自身免疫性糖尿病。值得注意的是，我们将定义时间方面以及关键细胞群 参与先天免疫反应。这些实验的结果将揭示特定的先天免疫 参与胰岛素炎和自身免疫性糖尿病发展的途径，并且对于 为 T1D 风险最大的个人制定预防策略。