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

项目摘要 好了！尽管经过数十年的密集研究，以自身免疫为特征的1型糖尿病(T1D) 胰腺中产生胰岛素的β细胞的破坏仍然是无法阻止的。了解 T1D发生的先天免疫机制对于制定预防策略至关重要。 剖析环境刺激之间的相互作用，如病毒感染、免疫反应和 胰岛素炎(T1D的一个关键病理特征)在人类中的发展是极具挑战性的。通过暂时地 在自身免疫性糖尿病的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 针对人类疾病进程的干预措施。 我们已经发现I型干扰素受体(IFNAR)是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生中起关键作用 断奶法律1WR1大鼠。我们将通过以下方式进一步确定I型干扰素在糖尿病发展中的作用 比较WT和IFNAR-/-大鼠的免疫细胞募集并检测转录图谱 单细胞水平。我们还将确定包括β细胞在内的胰岛内固有的干扰素信号是否参与了 WT与IFNAR-/-大鼠胰岛移植形成T1D的研究炎症途径 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细胞介素1 (IL-1)受体将预防I型干扰素依赖型糖尿病。我们将描述反腐败的机制。 发炎药水杨酸盐可预防糖尿病。我们计划使用CRISPR-Cas9基因创建一只基因敲除大鼠 编辑策略以检查炎症途径介导的对糖尿病发展的贡献 自身免疫性糖尿病。 通过建议的研究，我们将对免疫反应有一个基本的了解。 这会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体 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，并对 为T1D高危人群制定预防策略。

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.