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

项目摘要 !尽管经过数十年的深入研究，1型糖尿病（T1 D），其特征是自身免疫性 胰腺产生胰岛素的β细胞的破坏仍然无法预防。了解 T1 D发展的先天免疫机制对于开发预防策略至关重要。 剖析环境刺激之间的相互作用，如病毒感染，免疫反应，和 人的胰岛炎（T1 D的关键病理特征）的发展是极具挑战性的。通过在时间上 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异性的 针对人类疾病过程的干预措施。 我们已经发现，I型干扰素（IFN）受体（IFNAR），先天免疫的关键组成部分， 对病毒感染的反应，在病毒诱导的自身免疫性糖尿病的发展中起关键作用， LEW.1WR1断乳大鼠。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 单细胞水平。我们还将确定胰岛（包括β细胞）中固有的IFN信号是否有助于 通过在WT和IFNAR-/-大鼠之间进行胰岛移植来观察T1 D的发展。炎症通路 也参与自身免疫性糖尿病的发病机制。我们将确定阻断白细胞介素-1 （IL-1）受体将预防I型IFN非依赖性糖尿病。我们将描述抗- 炎性药物水杨酸可预防糖尿病。我们计划使用CRISPR-Cas9基因创造一种敲除大鼠 编辑策略，以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异性先天免疫 参与胰岛炎和自身免疫性糖尿病发展的途径， 为T1 D风险最高的个体制定预防策略。

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.