Biochemical Mechanism of Beta-Cell Destruction

自身免疫性糖尿病的特点是胰岛及其周围的炎症反应， 随后选择性破坏β细胞。这项研究的主要目标是阐明细胞 负责胰腺细胞死亡的机制并确定胰腺细胞死亡的机制 保护自己免受细胞因子和自由基介导的损伤。一氧化氮，主要介质 白细胞介素-1 (IL-1) 和干扰素- (IFN-) 对细胞功能的抑制作用，还可激活 保护细胞免受细胞因子介导的损伤的“恢复”途径。这是两者之间微妙的平衡 一氧化氮的毒性和保护作用最终决定-细胞对细胞因子-的敏感性 介导的损害。该提案的重点是阐明细胞因子刺激的细胞途径 - 细胞死亡，负责细胞从细胞因子和自由基介导的损伤中恢复的途径，以及 这些途径如何相互作用来决定细胞命运。具体目标有三个。 1. 检验细胞功能不可逆抑制与细胞功能开关相关的假设 细胞因子诱导的死亡从坏死到凋亡的机制以及一氧化氮的产生率， NAD 的细胞水平和 DNA 损伤的程度有助于这种机制的转换。 2. 检验一氧化氮激活细胞中的 AMPK 以及 AMPK 对于细胞内的 AMPK 至关重要的假设。 细胞从细胞因子和一氧化氮介导的损伤中“功能恢复”。 3. 检验 FoxO1 是控制细胞对细胞因子和细胞因子反应的主要调节因子的假设 一氧化氮。在细胞有能力从细胞因子介导的损伤中恢复的条件下， FoxO1 指导转录程序，保护细胞免受氧化应激。当-细胞是 FoxO1 致力于细胞因子介导的死亡，调节指导细胞的转录程序 细胞凋亡。 许多生物化学、分子生物学、免疫学、细胞生物学和转基因技术将 可用于研究一氧化氮介导细胞破坏的细胞途径和 参与保护细胞免受细胞因子介导的损伤的途径。希望有见解 从这些研究中了解细胞因子介导的损伤机制以及对这种损伤的保护 将影响旨在预防和治疗这种使人衰弱的治疗策略的设计 紊乱。

Autoimmune diabetes is characterized by an inflammatory reaction in and around pancreatic islets, followed by selective destruction of -cells. The broad goals of this research are to elucidate the cellular mechanisms that are responsible for pancreatic -cells death and to identify mechanisms by which -cells protect themselves against cytokine- and free radical-mediated damage. Nitric oxide, the primary mediator of the inhibitory actions of interleukin-1 (IL-1) and interferon- (IFN-) on -cell function, also activates a "recovery" pathway that protects -cells from cytokine-mediated damage. It is the delicate balance between the toxic and protective actions of nitric oxide that ultimately determine the susceptibility of -cells to cytokine- mediated damage. This proposal focuses on elucidating the cellular pathways by which cytokines stimulate - cell death, the pathways responsible for -cell recovery from cytokine- and free radical-mediated damage, and how these pathways interact to determine -cell fate. There are three specific aims. 1. To test the hypothesis that irreversible inhibition of -cell function is associated with a switch in the mechanism of cytokine-induced death from necrosis to apoptosis and that the rate of nitric oxide production, the cellular levels of NAD, and the extent of DNA damage contribute to this mechanistic switch. 2. To test the hypothesis that nitric oxide activates AMPK in -cells and that AMPK is essential for the "functional recovery" of -cells from cytokine- and nitric oxide-mediated damage. 3. To test the hypothesis that FoxO1 is a primary regulator controlling the response of -cells to cytokines and nitric oxide. Under conditions in which -cells have the ability to recover from cytokine-mediated damage, FoxO1 directs a transcriptional program affording -cells protection from oxidative stress. When -cells are committed to cytokine-mediated death, FoxO1 regulates a transcriptional program that directs -cell apoptosis. A number of biochemical, molecular biological, immunological, cell biological, and transgenic techniques will be utilized to investigate the cellular pathways through which nitric oxide mediates -cell destruction and the pathways that participate in the protection of -cells from cytokine-mediated damage. It is hoped that insights into the mechanisms of cytokine-mediated damage and protection from this damage gained from these studies will influence the design of therapeutic strategies aimed at the prevention and treatment of this debilitating disorder.