Protective Mechanisms in Pancreatic Beta-cells

项目摘要/摘要 胰腺细胞负责胰岛素的合成和分泌，以响应葡萄糖的挑战。 作为唯一能够表达和分泌胰岛素的细胞类型，它们对于有机体的生存至关重要。 由于它们是必需的，但它们的复制能力有限，这在进化上是有利的 -细胞具有保护自己免受各种细胞压力的机制。形成了一种 活性氧和氮物种(ROS和RNS)，如过氧化氢和一氧化氮，已经被 与糖尿病发展过程中细胞的死亡有关。事实上，在-细胞中产生的一氧化氮 对致炎细胞因子(IL-1β和干扰素-γ)的反应，抑制线粒体氧化磷酸化和 胰岛素分泌、过氧化氢引起蛋白质、脂质和dna的氧化，两者都会引起dna损伤。 如果损伤得不到修复，这可能会导致细胞死亡。此外，有人认为-细胞是 据报道，由于抗氧化剂水平较低，容易受到损害；然而，这一观点与几个 细胞的基本特征。ROS是由负责葡萄糖感应和 葡萄糖刺激的胰岛素分泌(线粒体氧化代谢)，其产生是直接的 与血糖浓度成正比。此外，这一途径对一氧化氮的抑制很敏感。 我们的中心假设是，因为β细胞是生物体生存所必需的，所以它们在进化上是 我们的长期目标是确定通过什么机制实现这一点 保护就会发生。有两个目的：(1)检验硫氧还蛋白/过氧化还蛋白抗氧化剂 系统促进β细胞的存活和功能，以及(2)检验IL-1信号促进 胰岛内分泌细胞的保护性反应。使用生化、分子、免疫学、遗传学和组学 这些研究将启动对胰腺β细胞保护机制的研究。 对抗氧化剂、自由基和环境挑战。拟议中的实验将在 K99阶段，由MCW的导师和咨询团队提供专业知识和技术援助，以及 将在过渡到独立的R00阶段后完成。我们认为保护的途径 将为治疗干预提供新的靶点，旨在 功能性β-细胞团和减轻或防止糖尿病的发展。

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.