Biochemical Mechanism of Beta-Cell Destruction

自身免疫性糖尿病的特征是胰岛及其周围的炎症反应， 然后选择性地破坏-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以及确定细胞死亡的机制 保护自己免受细胞因子和自由基介导的损害。一氧化氮，是血管生成的主要调节因子 白介素1(IL-1)和干扰素(干扰素-1)对细胞功能的抑制作用也激活了 保护细胞免受细胞因子介导的损伤的“恢复”途径。这是一种微妙的平衡 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 介入性损害。这项建议侧重于阐明细胞因子刺激- 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的命运。有三个具体目标。 1.检验细胞功能不可逆性抑制与细胞功能转换有关的假说 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速率， NAD的细胞水平和DNA损伤的程度有助于这种机制的转换。 2.验证一氧化氮激活细胞内AMPK的假设，以及AMPK对 细胞从细胞因子和一氧化氮介导的损伤中的“功能恢复”。 3.检验FoxO1是控制细胞对细胞因子反应的主要调节因子的假设，以及 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指导一个转录程序，为细胞提供免受氧化应激的保护。当-单元格是 致力于细胞因子介导的死亡，FoxO1调节一种转录程序，指导细胞 细胞凋亡。 许多生化、分子生物学、免疫学、细胞生物学和转基因技术将 被用来研究一氧化氮介导的细胞通路-细胞破坏和 参与保护细胞免受细胞因子介导的损伤的途径。希望有真知灼见 从这些研究中获得的细胞因子介导的损伤机制和对这种损伤的保护 将影响旨在预防和治疗这种衰弱的治疗策略的设计 无序。

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.