BIOCHEMICAL MECHANISM OF BETA-CELL DESTRUCTION

描述（改编自申请人摘要）：本研究在 这一修订后的提案仍然有一个广泛的目标，即阐明 与胰岛β细胞破坏相关的细胞机制 自身免疫性糖尿病 与性能相关的重要观察结果 这项研究的重点是围绕IL-1的良好特征的影响， 对胰岛β细胞功能的影响 IL-1抑制胰岛素分泌并靶向 线粒体酶的铁硫中心。 NO是一种效应分子 由IL-1诱导的β细胞iNOS表达产生。 INF伽马降低 刺激胰岛表达iNOS所需的IL-1浓度 并且与iNOS mRNA的稳定性增加有关。 在没有 IL-1 IFN γ不调节β细胞功能。 具体目标1将阐明所需的细胞信号传导机制， IL-1通过β细胞诱导iNOS表达并确定其机制 IFN γ引发并增强IL-1诱导的iNOS表达。 这一目标是基于P.I. IL-1选择性地 通过β细胞刺激诱导型一氧化氮合酶（iNOS）表达 IFN γ启动并增强IL-1诱导的iNOS表达。 因此，细胞因子诱导的iNOS表达和随后产生的 高水平的NO是β细胞破坏的机制之一。 特异性目标2将确定IL-1的细胞来源， IL-1、胰岛内IL-1释放的调控机制及其对胰岛功能的影响 胰岛内释放对β细胞功能的影响。 这一目标旨在 检验胰岛内巨噬细胞活化介导 导致胰岛β细胞破坏的初始事件。 具体目标3将确定iNOS和考克斯-2（考克斯）的细胞来源 催化生物合成途径中的第一反应， 生产中。 考克斯2是可诱导的，IL-1诱导COX 2，iNOS 刺激其活性）、NO是否激活考克斯-2以及考克斯-2和 iNOS参与胰岛炎症和β细胞损伤。 一个主要目标 目的是检验这一假设，即促炎性和破坏性 NO的作用直接参与胰岛炎症和B细胞损伤 自身免疫性糖尿病的NOD小鼠模型。

DESCRIPTION (Adapted from applicant's abstract): This research proposed in this revised submission continues to have the broad goal to elucidate the cellular mechanisms associated with pancreatic islet beta cell destruction in autoimmune diabetes. Important observations relevant to the performance of this research are centered around the well characterized effects of IL-1 on islet beta cell function. IL-1 inhibits insulin secretion and targets iron-sulfur centers of mitochondrial enzymes. NO is an effector molecule produced by IL-1 induced iNOS expression by beta cells. INF gamma reduces the concentration of IL-1 required to stimulate iNOS expression by islets and is associated with an increased stability of iNOS mRNA. In the absence of IL-1 IFN gamma does not modulate beta cell function. Specific aim 1 will elucidate the cellular signaling mechanisms required for IL-1 induced iNOS expression by beta cells and determine the mechanism by which IFN gamma primes for and potentiates IL-1 induced iNOS expression. This aim is based on the observations by the P.I. that IL-1 selectively stimulates inducible nitric oxide synthase (iNOS) expression by beta cells and that IFNgamma primes for and potentiates IL-1 induced iNOS expression. Therefore, cytokine induced iNOS expression and consequent production of high levels of NO is one mechanism of beta cell destruction. Specific aim 2 will determine the cellular source of IL-1, the isoforms of IL-1, the mechanisms controlling intra-islet release of IL-1 and the effects of intra-islet release on beta cell function. This aim is directed to testing the hypothesis that intra-islet macrophage activation mediates the initial events leading to islet beta cell destruction. Specific aim 3 will determine the cellular sources of iNOS and COX-2 (COX catalyzes the first reaction in the biosynthetic pathway responsible for the production of prostaglandins. COX 2 is inducible, IL-1 induces it and iNOS stimulates its activity), whether NO activates COX-2 and whether COX-2 and iNOS participate in islet inflammation and beta cell damage. A major goal of this aim is to test the hypothesis that proinflammatory and destructive actions of NO directly participate in islet inflammation and B cell damage in the NOD mouse model of autoimmune diabetes.