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Protective Mechanisms in Pancreatic Beta-cells

胰腺β细胞的保护机制

基本信息

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
项目类别：
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

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.

项目总结/文摘