The role of beta cell ATF6 in type 1 diabetes

β细胞ATF6在1型糖尿病中的作用

• 批准号: 10337931
• 负责人: Feyza Engin
• 金额: $ 38.21万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-24 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337931
• 关键词: ATF6 gene; Acute; Antioxidants; Apoptosis; Apoptotic; Autoimmune; B-Lymphocytes; Beta Cell; Binding; Biochemical; Biological Assay; Cell Communication; Cell Cycle Arrest; Cell Death; Cell Survival; Cell physiology; Cells; Cellular Stress; Chemicals; Chronic; Communities; DNA Damage; Data; Development; Diabetes Mellitus; Disease; Endoplasmic Reticulum; Environmental Risk Factor; Etiology; Exhibits; Exposure to; Failure; Future; Gene Expression; Gene Expression Profile; Genes; Genetic Models; Genetic Transcription; Goals; Graft Survival; Homeostasis; Human; Immune; Immune system; Inbred NOD Mice; Incidence; Individual; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Knowledge; Leukocytes; Light; M cell; Mediating; Membrane; Modeling; Molecular; Mus; Non obese; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Physiological; Play; Pre-Clinical Model; Proteins; Reagent; Regulation; Resources; Role; Signal Pathway; Signal Transduction; Stress; Structure of beta Cell of islet; System; T-Cell Activation; TP53 gene; Techniques; Testing; Therapeutic; Transcriptional Regulation; Up-Regulation; Work; acute stress; base; biological adaptation to stress; cell type; diabetes pathogenesis; endoplasmic reticulum stress; functional loss; improved; in vivo; insight; insulitis; islet; knowledge base; loss of function; migration; mouse model; novel; novel therapeutic intervention; pre-clinical; programs; promoter; protein misfolding; response; sensor; transcriptome; translational approach

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) results from autoimmune-mediated destruction of pancreatic β-cells. Despite its autoimmune etiology, emerging data suggest that intrinsic β-cell stress and defective adaptive stress responses can play an important role in the loss of functional β-cell mass in T1D. However, the molecular mechanisms by which the stress responses regulate β-cell death/survival in T1D have remained elusive, due primarily to a lack of in vivo preclinical genetic models, hindering the development of novel, effective, and alternative therapeutic strategies against T1D. Endoplasmic reticulum (ER) stress is caused by protein misfolding, chronic inflammation, and environmental factors. Upon ER stress, the unfolded protein response (UPR), a signaling cascade mediated by ER membrane-localized sensors ATF6, IRE1α and PERK, is triggered to re-establish cellular homeostasis. While these proteins induce adaptive responses under acute stress, under prolonged stress the UPR initiates apoptosis. The decision mechanisms for switching between adaptive and maladaptive responses, and the specific adaptive or maladaptive functions of each UPR sensors in distinct cell types and disease contexts, are yet to be uncovered. To this end, we have recently deleted Atf6 in β-cells (Atf6β-/-) of a well-established preclinical T1D model, non-obese diabetes (NOD) mice, before the initiation of islet inflammation. Remarkably, Atf6β-/- mice exhibited significantly reduced diabetes incidence . Transcriptome analysis of sorted β-cells of NOD Atf6β-/- mice revealed p53/p21 signaling pathway as the top enriched pathway and uncovered a previously not recognized pro-survival adaptative program in β-cells during T1D progression, which ultimately confers protection from T1D. Atf6β-/- mice also showed reduced insulitis and increased expression of immune inhibitory markers in β- cells, suggesting a non-cell autonomous effect of loss of function of Atf6 on the immune system. Therefore, in light of these data we hypothesize that upon loss of Atf6 in β-cells, a novel adaptive program governed by p21 signaling prevails, which in a non-cell autonomous manner alters β-cells-immune cell communication. Moreover, we hypothesize that under acute versus mild and prolonged stress conditions ATF6 triggers distinct transcriptional programs to regulate cellular homeostasis in human β-cells. Here, by utilizing a mouse model and human islets combined with a comprehensive toolbox of techniques and novel reagents we propose to (i) identify the mechanisms, by which loss of Atf6 in b-cells impact, b-cell-immune cell crosstalk (ii) define the mechanisms of p21 upregulation and reduced pathology in Atf6β-/- mice, and (iii) determine the ATF6-mediated stress adaptation mechanisms in human islets exposed to acute and prolonged ER stress. The successful completion of these studies will fill an existing gap in our knowledge base regarding the function of Atf6 in β-cells, identify a novel mechanism for β-cell-immune cell crosstalk, and significantly improve our understanding of mechanisms of β- cell failure in T1D. It will also provide mechanistic insight for future studies and support alternative translational strategies for T1D that target the b-cell UPR.

项目摘要/摘要 1型糖尿病（T1D）是由于自身免疫介导的胰腺β细胞破坏而引起的。尽管有它 自身免疫性病因，新兴数据表明固有的β细胞应力和缺陷的适应性应力反应 在T1D中功能性β细胞质量的丧失中可以发挥重要作用。但是，分子机制通过 压力反应调节T1D中的β细胞死亡/生存率仍然难以捉摸，这是由于缺乏主要的 体内临床前遗传模型，阻碍了新颖，有效和替代性治疗策略的发展 反对T1D。内塑性网状（ER）应力是由蛋白质折叠，慢性炎症和 环境因素。在ER应力下，展开的蛋白质反应（UPR），一种由ER介导的信号传导级联 触发膜 - 定位传感器ATF6，IRE1α和PERK，以重新建立细胞稳态。而这些 蛋白质在急性应激下诱导适应性反应，在延长的压力下，UPR引发了凋亡。 自适应和适应不良反应之间切换的决策机制，以及特定的适应性或 在不同的细胞类型和疾病环境中，每个UPR传感器的适应不良功能尚未 裸露。 为此， 我们最近删除了公认的临床前T1D中β细胞（ATF6β-/ - ）中的ATF6 在胰岛注射开始之前，模型，非肥胖糖尿病（NOD）小鼠。值得注意的是，ATF6β-/ - 小鼠 表现出明显降低的糖尿病发病率。 NODATF6β-/ - 小鼠的分类β细胞的转录组分析 揭示了p53/p21信号通路作为顶部富集途径，并发现了先前未识别的 T1D进展过程中的β细胞的促生物自适应程序，最终有助于保护 T1D。 ATF6β-/ - 小鼠还显示胰岛素降低和β-中免疫抑制性标记的表达增加 细胞，表明ATF6功能丧失对免疫系统的非电池自主效应。因此，在 这些数据的光线我们假设β细胞中ATF6丢失后，由P21控制的新型自适应程序 信号传导盛行，以非细胞自主方式改变了β细胞免疫细胞通信。而且， 我们假设在急性与轻度和长时间应力条件下ATF6触发不同的转录 调节人β细胞中细胞稳态的程序。在这里，使用鼠标模型和人类胰岛 结合一个全面的技术和新型试剂工具箱，我们建议（i）确定 机理，B细胞中ATF6的损失影响，B细胞免疫细胞串扰（II）定义了P21的机制 ATF6β - / - 小鼠的上调和降低的病理，（iii）确定ATF6介导的应激适应性 人类胰岛的机制暴露于急性和延长的质网应激。这些成功完成 研究将填补我们关于β细胞中ATF6功能的知识基础的现有空白，确定一种新颖 β-Cell-免疫细胞串扰的机制，并显着提高了我们对β-机制的理解 T1D中的细胞衰竭。它还将为未来的研究提供机械见解，并支持替代性翻译 针对B细胞UPR的T1D策略。