Paradoxical Roles of Reactive Oxygen Species in Pancreatic Beta-Cell Function

活性氧在胰腺 β 细胞功能中的矛盾作用

• 批准号: 7643808
• 负责人: Jingbo Pi
• 金额: $ 8.21万
• 依托单位: THE HAMNER INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643808
• 关键词: Antioxidants; Area; Cell physiology; Cells; Chronic; Confocal Microscopy; Coupled; Data; Defense Mechanisms; Development; Development Plans; Diabetes Mellitus; Disease; Enzymes; Etiology; Event; Exhibits; Failure; Fluorescent Probes; Fostering; Functional disorder; Future; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Glucose; Goals; Grant; Hand; Hand functions; Hormonal; Hydrogen Peroxide; Insulin; Intervention; Knock-out; Knowledge; Lead; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Monitor; Mus; Nitric Oxide; Nuclear; Nutrient; Oral; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxidative Stress Induction; Pancreas; Pathogenesis; Physiological; Play; Preventive; Process; Production; Reactive Oxygen Species; Recombinants; Research; Research Personnel; Research Project Grants; Resources; Role; Scientist; Signal Transduction; Structure of beta Cell of islet; Superoxides; System; Testing; Time; UCP2 protein; Writing; blood glucose regulation; career; career development; catalase; cell injury; design; experience; glucose metabolism; glucose production; glutathione peroxidase; insight; insulin secretion; islet; knowledge base; mouse model; overexpression; oxidative damage; relating to nervous system; research study; response; stressor; transcription factor; treatment strategy; type I and type II diabetes; vector

DESCRIPTION (provided by applicant): The long-term goal of Dr. Jingbo Pi is to become a successful independent investigator in the research field of diabetes. The large majority of Dr. Pi's time will be spent on the research project that he has described in his proposal on reactive oxygen species and (-cell function (summarized below in the Project Summary). This experience will provide him with both the theoretical and practical knowledge base upon which to build a career as an independent investigator in this area. The major immediate goals in his career development plan are (i) enrichment of his knowledge and research experience in the field of diabetes; (ii) develop excellence in scientific presentation, both oral and written; and (iii) grantsmanship and how to best organize the necessary resources and collaborators to successfully pursue future independent studies. Project Summary: Impaired metabolic signal transduction that mediates insulin secretion is fundamental in the pathophysiology of diabetes. Identification of valid targets for intervention in the treatment of diabetes requires knowledge of the metabolic signals that lead to stimulation of insulin secretion as well as its failure. This grant focuses on the roles of reactive oxygen species (ROS) as putative signals mediating glucose-stimulated insulin secretion (GSIS). There are two specific aims: (i) Test the hypothesis that ROS, in the low physiological range, are additional metabolic signals that regulate a cytosolic redox network to modulate insulin secretion; (ii) Test the hypothesis that antioxidant response mediated by transcription factor Nrf2 enhances cellular ROS scavenging activity and thus negatively regulates GSIS. The unique features of pancreatic (-cells, with relatively low expression and activity of many of antioxidant enzymes, provide a sensitive system for ROS/redox signaling. Importantly, the generation of ROS, which have emerged as physiological mediators of many cellular responses, is coupled to oxidative mitochondrial metabolism. We propose to (i) investigate the modulatory effect of glucose on intracellular ROS/redox signaling and the correlation with GSIS in INS-1 (832/13) cells and isolated intact mouse islets; (ii) evaluate the stimulation effects of ROS on insulin secretion and the inhibition effect of antioxidants on GSIS in these models; (iii) examine the effects of targeted gene disruption of Nrf2 or UCP2 on ROS/redox signaling and GSIS. Nrf2 is a central regulator in both constitutive and inducible gene expression of antioxidant enzymes, whereas UCP2 has been recognized as a negative regulator of mitochondria-derived ROS. Relevance: This project will help to foster the development of a successful scientist specializing in diabetes research. His currently proposed and future studies will contribute new insights into the mechanisms of diabetes and hopefully advance preventive measures and treatment strategies for this disease.

描述（由申请人提供）： Jingbo Pi博士的长期目标是成为糖尿病研究领域的成功独立研究者。 PI博士的大部分时间都将花在他在他对活性氧物种的提议中所描述的研究项目上，并且（-Cell功能（以下在项目摘要中进行了摘要）。这一经验将为他提供理论和实践知识的基础，以在该领域建立一个独立研究者的职业，这是他职业发展计划的主要研究。口头和（iii）授予技巧的科学表现卓越，以及如何最好地组织必要的资源和合作者，以成功地追求未来的独立研究。 项目摘要：介导胰岛素分泌的代谢信号转导受损是糖尿病病理生理学的基础。确定干预糖尿病治疗的有效靶标需要了解导致胰岛素分泌及其失败的代谢信号。该赠款的重点是活性氧（ROS）作为介导葡萄糖刺激的胰岛素分泌（GSIS）的推定信号。有两个具体的目的：（i）检验以下假设：在低生理范围内的ROS是调节胞质氧化还原网络以调节胰岛素分泌的其他代谢信号； （ii）检验以下假设：转录因子NRF2介导的抗氧化剂反应增强了细胞ROS清除活性，从而对GSI进行负调节。胰腺的独特特征（ - 许多抗氧化剂的表达和活性相对较低，为ROS/REDOX信号传导提供了一个敏感的系统。重要的是，重要的是，ROS的产生已作为许多细胞反应的生理介导者出现，以氧化为氧化的线粒体启用氧化代码。 ROS/REDOX信号与INS-1（832/13）细胞中的GSIS和孤立的小鼠胰岛的相关性评估ROS对胰岛素分泌的刺激作用，抗氧化剂对GSI的抑制作用对这些模型的抑制作用（III）。抗氧化酶的本构和诱导基因表达中的调节剂，而UCP2被认为是线粒体衍生的ROS的负调节剂。 相关性：该项目将有助于促进专门研究糖尿病研究的成功科学家的发展。他目前提出的研究和未来的研究将为糖尿病的机制提供新的见解，并希望推动对该疾病的预防措施和治疗策略。