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: 10663345
• 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/10663345
• 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; Repression; Resources; Role; Signal Pathway; Signal Transduction; Sorting; Stress; Structure of beta Cell of islet; System; T-Cell Activation; TP53 gene; Techniques; Testing; Therapeutic; Transcriptional Regulation; Up-Regulation; Work; acute stress; biological adaptation to stress; cell type; coping; diabetes pathogenesis; endoplasmic reticulum stress; functional loss; gene repression; 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.

项目概要/摘要 1 型糖尿病 (T1D) 是由自身免疫介导的胰腺 β 细胞破坏引起的。尽管其 自身免疫病因学，新出现的数据表明，内在的β细胞应激和有缺陷的适应性应激反应 在 T1D 中功能性 β 细胞质量的丧失中发挥重要作用。然而，分子机制通过 应激反应在 T1D 中调节 β 细胞死亡/存活的机制仍然难以捉摸，主要是由于缺乏 体内临床前遗传模型，阻碍了新颖、有效和替代治疗策略的开发 对抗 T1D。内质网 (ER) 应激是由蛋白质错误折叠、慢性炎症和 环境因素。内质网应激时，未折叠蛋白反应 (UPR)，这是由内质网介导的信号级联反应 膜定位传感器 ATF6、IRE1α 和 PERK 被触发以重建细胞稳态。虽然这些 蛋白质在急性应激下诱导适应性反应，在长期应激下，UPR 启动细胞凋亡。这 在适应性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适应性反应 每个 UPR 传感器在不同细胞类型和疾病背景下的适应不良功能尚未确定 裸露。 为此， 我们最近删除了临床前 T1D 的 β 细胞 (Atf6β-/-) 中的 Atf6 模型，非肥胖糖尿病（NOD）小鼠，在胰岛炎症开始之前。值得注意的是，Atf6β-/- 小鼠 表现出显着降低的糖尿病发病率。 NOD Atf6β-/- 小鼠分选 β 细胞的转录组分析 揭示了 p53/p21 信号通路是最富集的通路，并发现了以前未被识别的通路 T1D 进展期间 β 细胞中的促生存适应性程序，最终提供保护 T1D。 Atf6β-/- 小鼠还表现出胰岛素炎的减轻和 β- 中免疫抑制标记物表达的增加。 细胞，表明 Atf6 功能丧失对免疫系统产生非细胞自主效应。因此，在 根据这些数据，我们假设 β 细胞中 Atf6 丢失后，会出现一种由 p21 控制的新型适应性程序 信号传导占主导地位，它以非细胞自主的方式改变β细胞-免疫细胞的通讯。而且， 我们假设在急性应激条件下与轻度应激条件下和长期应激条件下 ATF6 会触发不同的转录 调节人类 β 细胞细胞稳态的程序。在这里，通过利用小鼠模型和人类胰岛 结合技术和新颖试剂的综合工具箱，我们建议（i）确定 b 细胞中 Atf6 缺失影响 b 细胞-免疫细胞串扰的机制 (ii) 定义了 p21 的机制 Atf6β-/- 小鼠中的上调和病理减少，以及 (iii) 确定 ATF6 介导的应激适应 暴露于急性和长期内质网应激的人类胰岛的机制。这些工作的顺利完成 研究将填补我们知识库中关于 Atf6 在 β 细胞中的功能的现有空白，确定一种新的 β-细胞-免疫细胞串扰机制，并显着提高我们对β-细胞-免疫细胞串扰机制的理解 T1D 细胞衰竭。它还将为未来的研究提供机制见解并支持替代转化 针对 b 细胞 UPR 的 T1D 策略。

项目成果

Analysis of Half a Billion Datapoints Across Ten Machine-Learning Algorithms Identifies Key Elements Associated With Insulin Transcription in Human Pancreatic Islet Cells.

• DOI: 10.3389/fendo.2022.853863
• 发表时间: 2022
• 期刊: Frontiers in endocrinology
• 影响因子: 5.2
• 作者: Wong WKM;Thorat V;Joglekar MV;Dong CX;Lee H;Chew YV;Bhave A;Hawthorne WJ;Engin F;Pant A;Dalgaard LT;Bapat S;Hardikar AA
• 通讯作者: Hardikar AA

An accomplice more than a mere victim: The impact of β-cell ER stress on type 1 diabetes pathogenesis.

• DOI: 10.1016/j.molmet.2021.101365
• 发表时间: 2021-12
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Sahin GS;Lee H;Engin F
• 通讯作者: Engin F