BIOCHEMICAL MECHANISM OF BETA-CELL DESTRUCTION
β 细胞破坏的生化机制
基本信息
- 批准号:6489690
- 负责人:
- 金额:$ 22.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-01-01 至 2002-12-31
- 项目状态:已结题
- 来源:
- 关键词:NOD mouse biological signal transduction clinical research cytokine receptors cytotoxicity enzyme inhibitors gene expression glucose metabolism insulin insulin dependent diabetes mellitus interferon gamma interleukin 1 laboratory rat leukocyte activation /transformation macrophage messenger RNA nitric oxide nitric oxide synthase nuclear factor kappa beta pancreatic islet function pancreatic islets prostaglandin endoperoxide synthase protein biosynthesis protein tyrosine kinase receptor binding tissue /cell culture
项目摘要
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.
描述(改编自申请人的摘要):这项研究建议于
这份修订后的意见书仍然有一个广泛的目标,即澄清
与胰岛β细胞破坏相关的细胞机制
自身免疫性糖尿病。与绩效相关的重要观察
这项研究的中心是IL-1的典型作用
胰岛β细胞功能。IL-1抑制胰岛素分泌及其靶点
线粒体酶的铁硫中心。一氧化氮是一种效应器分子
由IL-1诱导β细胞表达iNOS产生。Inf伽马降低
胰岛诱导型一氧化氮合酶表达所需的IL-1浓度
并与iNOS mRNA的稳定性增加有关。在缺席时
IL-1干扰素-γ对β细胞功能无调节作用。
具体目标1将阐明所需的细胞信号机制
IL-1诱导β细胞诱导型一氧化氮合酶表达及其机制的研究
其中干扰素-γ启动并增强IL-1诱导的iNOS表达。
这一目的是基于P.I.的观察,即IL-1选择性地
β细胞刺激诱导型一氧化氮合酶(INOS)表达
IL-1诱导的iNOS表达可通过干扰素-γ来启动和增强。
因此,细胞因子诱导了iNOS的表达,从而产生了
高水平的NO是β细胞破坏的一种机制。
特异性目标2将确定IL-1的细胞来源,其亚型
IL-1、控制胰岛内IL-1释放的机制及其作用
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激活介导
导致胰岛β细胞破坏的初始事件。
特殊目标3将确定iNOS和COX-2(COX)的细胞来源
催化生物合成途径中的第一反应,负责
前列腺素的生产。COX-2是可诱导的,IL-1诱导它和iNOS
刺激其活性),NO是否激活COX-2,以及COX-2和
INOS参与胰岛炎症和胰岛β细胞损伤。一个主要目标
其目的是检验促炎症和破坏性的假设
NO直接参与胰岛炎症和B细胞损伤
在自身免疫性糖尿病的NOD小鼠模型中。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('JOHN A CORBETT', 18)}}的其他基金
Unfolded Protein Response: Regulator of Human beta-cells
未折叠蛋白反应:人类 β 细胞的调节因子
- 批准号:
6830872 - 财政年份:2004
- 资助金额:
$ 22.84万 - 项目类别:
Unfolded protein response as a regulator of human beta-*
未折叠的蛋白质反应作为人类β-*的调节剂
- 批准号:
6916219 - 财政年份:2004
- 资助金额:
$ 22.84万 - 项目类别:
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