Protective Mechanisms in Pancreatic Beta-cells

胰腺β细胞的保护机制

• 批准号: 10283289
• 负责人: Jennifer Susan Stancill
• 金额: $ 9万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283289
• 关键词: Advisory Committees; Affect; Antioxidants; Antiviral Agents; Attenuated; Beta Cell; Biochemical; Blood Glucose; Cell Death; Cell Respiration; Cell Survival; Cell physiology; Cells; Cellular Stress; Characteristics; DNA; DNA Damage; Data; Development; Diabetes Mellitus; Diffuse; Diffusion; Endocrine; Environmental Protection; Enzymes; Free Radicals; Gene Expression; Genetic; Glucose; Goals; Human; Hydrogen Peroxide; Immunologics; Insulin; Interferon Type II; Interleukin-1; Interleukin-1 Receptors; Interleukin-1 beta; Investigation; Knock-out; Knockout Mice; Lead; Lipids; Mentors; Mitochondria; Modeling; Molecular; Mus; NOS2A gene; Nitric Oxide; Nitrogen; Organism; Oxidants; Oxidative Phosphorylation; Oxygen; Pancreas; Pathway interactions; Peroxonitrite; Phase; Play; Production; Proteins; Publishing; Rattus; Reaction; Role; Signal Transduction; Signaling Molecule; Structure of beta Cell of islet; Superoxides; System; TXN gene; Testing; acute infection; animation; cell type; cytokine; diabetes pathogenesis; experience; experimental study; gene repression; in vivo; insulin secretion; insulinoma; islet; mouse model; new therapeutic target; oxidation; peroxiredoxin; peroxiredoxin I; preservation; prevent; response; therapy design; thioredoxin reductase 1

Project Summary/Abstract Pancreatic -cells are responsible for synthesis and secretion of insulin in response to a glucose challenge. They are essential for survival of the organism as the only cell type capable of expressing and secreting insulin. Since they are essential, yet they have a limited capacity to replicate, it would be evolutionarily advantageous for -cells to possess mechanisms to protect themselves from a variety of cellular stresses. The formation of reactive oxygen and nitrogen species (ROS and RNS), such as hydrogen peroxide and nitric oxide, have been implicated in the demise of -cells during diabetes development. Indeed, nitric oxide, produced in -cells in response to proinflammatory cytokines (IL-1β and IFN-γ), inhibits mitochondrial oxidative phosphorylation and insulin secretion, hydrogen peroxide causes oxidation of proteins, lipids, and DNA, and both cause DNA damage that can lead to cell death if the damage is not repaired. Furthermore, it has been suggested that -cells are vulnerable to damage due to reportedly low levels of antioxidants; however, this view is at odds with several fundamental characteristics of -cells. ROS are produced by the pathway responsible for glucose sensing and glucose-stimulated insulin secretion (mitochondrial oxidative metabolism), and their production is directly proportional to the blood glucose concentration. Additionally, this pathway is sensitive to inhibition by nitric oxide. Our central hypothesis is that, because they are essential for organism survival, β-cells are evolutionarily programmed to be protected from damage, and our long-term goal is to identify the mechanisms by which this protection occurs. There are two aims: (1) to test the hypothesis that the thioredoxin/peroxiredoxin antioxidant system promotes β-cell survival and function, and (2) to test the hypothesis that IL-1 signaling promotes protective responses in islet endocrine cells. Using biochemical, molecular, immunological, genetic, and omics approaches, these studies will initiate investigations into the mechanisms by which pancreatic β-cells protect themselves against oxidant, free radical, and environmental challenges. Proposed experiments will begin during the K99 phase, with expertise and technical assistance provided by the mentor and advisory team at MCW, and will be completed upon transition to the independent R00 phase. We believe that the pathways of protection that are identified in these studies will provide novel targets for therapeutic intervention designed to preserve functional β-cell mass and attenuate or prevent diabetes development.

项目摘要/摘要 胰腺细胞负责胰岛素的合成和分泌，以应对葡萄糖挑战。 它们对于生存的生存至关重要，是唯一能够表达和分泌胰岛素的细胞类型。 由于它们是必不可少的，但是它们的复制能力有限，因此在进化上是有利的 细胞具有保护自己免受各种细胞应激的机制。形成 活性氧和氮种（ROS和RN），例如过氧化氢和一氧化氮已经是 在糖尿病发育过程中实施了细胞的消亡。实际上，在细胞中产生的一氧化氮 对促炎细胞因子（IL-1β和IFN-γ）的反应，抑制线粒体氧化磷酸化和 胰岛素分泌，过氧化氢会导致蛋白质，脂质和DNA的氧化，两者都会引起DNA损伤 如果未修复损坏，那可能会导致细胞死亡。此外，有人建议细胞是 据报道，抗氧化剂水平较低，容易受到损害；但是，这种观点与几个 细胞的基本特征。 ROS由负责葡萄糖灵敏度的途径产生 葡萄糖刺激的胰岛素分泌（线粒体氧化代谢），它们的产生直接 与血糖浓度成正比。另外，该途径对一氧化氮抑制敏感。 我们的中心假设是，由于它们对于生物的生存至关重要，因此β细胞在进化上是 已编程以保护免受损害，我们的长期目标是确定该机制 发生保护。有两个目的：（1）检验硫氧还蛋白/过氧蛋白抗氧化剂的假设 系统促进β细胞的存活和功能，（2）测试IL-1信号促进的假设 胰岛内分泌细胞中的保护性反应。使用生化，分子，免疫学，遗传和幻象 方法是，这些研究将开始研究胰腺β细胞保护的机制 自己反对氧化物，自由基和环境挑战。建议的实验将在 K99阶段，具有MCW心理和咨询团队提供的专业知识和技术援助， 将在过渡到独立R00阶段时完成。我们相信保护途径 在这些研究中确定将为保存的热干预提供新的目标 功能性β细胞质量并减弱或预防糖尿病的发育。