Protective Mechanisms in Pancreatic Beta-cells

项目总结/摘要 胰腺β细胞负责响应葡萄糖刺激而合成和分泌胰岛素。 作为唯一能够表达和分泌胰岛素的细胞类型，它们对生物体的生存至关重要。 既然它们是必需的，但它们的复制能力有限， 使细胞具有保护自身免受各种细胞应激的机制。的形成 活性氧和氮物质（ROS和RNS），如过氧化氢和一氧化氮，已经被广泛应用于生物医学领域。 与糖尿病发展过程中β细胞的死亡有关。事实上，一氧化氮，产生于胰岛细胞， 对促炎细胞因子（IL-1β和IFN-γ）的应答，抑制线粒体氧化磷酸化， 胰岛素分泌，过氧化氢导致蛋白质，脂质和DNA氧化，两者都导致DNA损伤 如果损伤得不到修复，会导致细胞死亡此外，有人提出，β细胞是 容易受到损害，由于据报道，低水平的抗氧化剂;然而，这一观点与几个 细胞的基本特征。ROS由负责葡萄糖传感的途径产生， 葡萄糖刺激的胰岛素分泌（线粒体氧化代谢），它们的产生是直接 与血糖浓度成正比。此外，该途径对一氧化氮的抑制敏感。 我们的中心假设是，由于β细胞对生物体的生存至关重要，因此它们在进化上是 我们的长期目标是确定这种机制， 保护发生。目的有二：（1）检验硫氧还蛋白/过氧化物氧还蛋白抗氧化剂 系统促进β细胞存活和功能，以及（2）测试IL-1信号传导促进β细胞存活和功能的假设。 胰岛内分泌细胞的保护反应。利用生物化学、分子学、免疫学、遗传学和组学 这些研究将启动对胰腺β细胞保护的机制的研究。 自身对抗氧化剂、自由基和环境挑战。拟议的实验将于2009年12月开始。 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R 00阶段时完成。我们认为，保护的途径， 这些研究中确定的新靶点将为治疗干预提供新靶点， 功能性β细胞群并减弱或预防糖尿病发展。

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.