Protective Mechanisms in Pancreatic Beta-cells

胰腺β细胞的保护机制

基本信息

批准号：
10466901
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
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10466901
关键词：
Advisory Committees Affect Antioxidants 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

项目摘要

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.

项目概要/摘要胰腺  细胞负责合成和分泌胰岛素以响应葡萄糖挑战。它们对于生物体的生存至关重要，因为它们是唯一能够表达和分泌胰岛素的细胞类型。由于它们是必需的，但它们的复制能力有限，因此在进化上将是有利的 -细胞拥有保护自身免受各种细胞应激的机制。活性氧和氮物种（ROS 和 RNS），例如过氧化氢和一氧化氮，已被事实上，一氧化氮在糖尿病发展过程中与  细胞的死亡有关。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、过氧化氢导致蛋白质、脂质和DNA氧化，两者都会造成DNA损伤如果损伤得不到修复，可能会导致细胞死亡。此外，有人认为  细胞会死亡。据报道，由于抗氧化剂含量低，容易受到损害；然而，这种观点与一些人不一致。 -细胞的基本特征是由负责葡萄糖传感和的途径产生的。葡萄糖刺激胰岛素分泌（线粒体氧化代谢），其产生直接此外，该途径对一氧化氮的抑制敏感。我们的中心假设是，由于 β 细胞对于生物体的生存至关重要，因此它们在进化上是编程以防止损坏，我们的长期目标是确定这种机制发生保护作用有两个目的：（1）检验硫氧还蛋白/过氧化氧还蛋白抗氧化剂的假设。系统促进 β 细胞存活和功能，以及 (2) 检验 IL-1 信号传导促进的假设利用生物化学、分子、免疫学、遗传学和组学研究胰岛内分泌细胞的保护性反应。这些研究将启动对胰腺 β 细胞保护机制的研究拟议的实验将在期间开始。 K99 阶段，由 MCW 的导师和咨询团队提供专业知识和技术援助，以及我们相信，保护途径将在过渡到独立 R00 阶段时完成。这些研究中确定的将为治疗干预提供新的目标，旨在保护功能性 β 细胞群并减轻或预防糖尿病的发展。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

β-cell-selective inhibition of DNA damage response signaling by nitric oxide is associated with an attenuation in glucose uptake.

DOI：
10.1016/j.jbc.2023.102994
发表时间：
2023-03
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Yeo, Chay Teng;Kropp, Erin M.;Hansen, Polly A.;Pereckas, Michael;Oleson, Bryndon J.;Naatz, Aaron;Stancill, Jennifer S.;Ross, Kyle A.;Gundry, Rebekah L.;Corbett, John A.
通讯作者：
Corbett, John A.