Biochemical Mechanism of Beta-Cell Destruction

β细胞破坏的生化机制

• 批准号: 9034568
• 负责人: JOHN A CORBETT
• 金额: $ 35.96万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9034568
• 关键词: Apoptotic; Attenuated; Autoimmune Diabetes; Autoimmune Process; Beta Cell; Biochemical; Biological; Cell Death; Cell Fate Control; Cell Respiration; Cell Survival; Cell physiology; Cells; Cessation of life; Cytoprotection; DNA Damage; DNA Repair; DNA Single Strand Break; Deacetylase; Development; Diabetes Mellitus; Equilibrium; Free Radicals; Funding; Gene Expression; Goals; Health; Hydrogen Peroxide; Individual; Induction of Apoptosis; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interferons; Interleukin-1; Islets of Langerhans; Lead; Mediating; Mediator of activation protein; Mitochondria; Molecular; Nature; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Pancreas; Pathway interactions; Peroxonitrite; Play; Process; Production; Reaction; Reactive Nitrogen Species; Reactive Oxygen Species; Recovery; Research; Role; Signal Transduction; Superoxides; Techniques; Testing; Therapeutic; Time; Transgenic Organisms; ataxia telangiectasia mutated protein; cell injury; cytokine; design; forkhead protein; functional disability; functional loss; insight; repaired; response

DESCRIPTION (provided by applicant): Autoimmune diabetes is characterized by the selective destruction of ¿-cells that occurs during an inflammatory reaction in and around pancreatic islets. Inflammatory cytokines, released during this process, impair ¿-cell function and can induce ¿-cell death. Cytokines have also been implicated in the loss of functional ¿-cell mass during the development of type 2 diabetes. The broad goals of this research are to elucidate the cellular mechanisms that are responsible the functional impairment and death of pancreatic ¿-cell following cytokine treatment, and to identify pathways by which ¿-cells protect themselves against cytokine-mediated damage. Reactive nitrogen species (RNS; e.g., nitric oxide) are primary mediators of the damaging actions of interleukin-1 (IL-1) and interferon (IFN)-??on ¿-cell function and viability. We have shown that nitric oxide can also activate "protective pathways" that lead to the recovery of insulin secretory function, mitochondrial oxidative metabolism, and the repair of damaged DNA. It is the delicate balance between the toxic and protective actions of RNS, produced by ¿-cells in response to cytokines that ultimately determines whether these cells survive or die. This proposal will elucidate the pathways that control ¿-cell fate following cytokine treatment. There are three specific aims: 1) To test the hypothesis that the response of ¿-cells to cytokine treatment is determined by a) the form of reactive oxygen species (ROS) or reactive nitrogen species (RNS) produced, and b) the ability of ROS and RNS to selectively regulate signaling cascades that control cellular repair/protective pathways or activate cell death cascades; 2) To test the hypothesis that Ataxia telangiectasia mutated (ATM) plays a primary role in regulating the response(s) of ¿-cells to cytokine- and nitric oxide-mediated damage; 3) To test the hypothesis that the activation status of SIRT1 determines whether ¿-cells respond to cytokine treatment with the induction of "protective pathways" or the stimulation of cell death cascades. A number of biochemical, molecular, immunological, cell biological and transgenic techniques will be utilized to investigate the cellular pathways through which nitric oxide and its reactive intermediates mediate ¿-cell damage and the pathways that participate in the protection of ¿-cells from cytokine-induced damage. It is hoped that insights into the mechanisms controlling the response of ¿-cells to cytokines that are gained from these studies will influence the design of therapeutic strategies aimed at attenuating the loss of functional ¿-cell mass during the development of diabetes.

描述（由申请人提供）：自身免疫性糖尿病的特征是在胰岛内和周围的炎症反应期间发生的对胰岛细胞的选择性破坏。在此过程中释放的炎性细胞因子损害了细胞功能，并可诱导细胞死亡。细胞因子也与2型糖尿病发展过程中功能性细胞团的丧失有关。本研究的广泛目标是阐明细胞因子治疗后胰腺<$-细胞功能受损和死亡的细胞机制，并确定<$-细胞保护自身免受精氨酸介导的损伤的途径。活性氮物质（RNS;例如，一氧化氮）是白细胞介素-1（IL-1）和干扰素（IFN-γ）损伤作用的主要介质。对细胞功能和生存能力的影响。我们已经证明，一氧化氮也可以激活“保护途径”，导致胰岛素分泌功能的恢复，线粒体氧化代谢和受损DNA的修复。正是RNS的毒性和保护作用之间的微妙平衡，RNS是由细胞对细胞因子的反应产生的，最终决定了这些细胞的生存或死亡。该建议将阐明细胞因子治疗后控制细胞命运的途径。有三个具体目标：1）检验以下假设：细胞对细胞因子处理的反应由a）产生的活性氧（ROS）或活性氮（RNS）的形式，和B）ROS和RNS选择性调节控制细胞修复/保护途径或激活细胞死亡级联的信号级联的能力决定; 2）为了验证共济失调毛细血管扩张突变（ATM）在调节细胞对细胞因子和一氧化氮介导的损伤的反应中起主要作用的假设; 3）为了验证SIRT 1的激活状态决定了SIRT 1是否被激活的假设。- 细胞通过诱导“保护性途径”或刺激细胞死亡级联反应来响应细胞因子处理。许多生物化学，分子，免疫学，细胞生物学和转基因技术将被用来调查的细胞途径，通过它的一氧化氮和它的反应中间体介导的？细胞损伤和参与保护？细胞从精氨酸诱导的损伤的途径。希望从这些研究中获得的对控制<$-细胞对细胞因子的反应的机制的见解将影响旨在减轻糖尿病发展期间功能性<$-细胞质量损失的治疗策略的设计。