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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：
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
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/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&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