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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

基本信息

批准号：
10431826
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
项目类别：
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/10431826
关键词：
Anti-Inflammatory 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&apos 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

项目摘要

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。