Biochemical Mechanism of Beta-Cell Destruction
β细胞破坏的生化机制
基本信息
- 批准号:8109630
- 负责人:
- 金额:$ 20.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-07-15 至 2011-06-30
- 项目状态:已结题
- 来源:
- 关键词:ApoptosisAutoimmune DiabetesBeta CellBiochemicalBiologicalCell DeathCell physiologyCellsCessation of lifeCommitCytoprotectionDNA DamageDiseaseEquilibriumFree RadicalsGoalsInflammatoryInterferonsInterleukin-1Islets of LangerhansMediatingMediator of activation proteinMolecularNecrosisNitric OxideOxidative StressPancreasPathway interactionsPredispositionPreventionProductionReactionRecoveryRecovery of FunctionResearchTechniquesTestingTherapeuticTransgenic Organismscytokinedesigninsightprogramsresponse
项目摘要
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.
自身免疫性糖尿病的特征在于胰岛内和周围的炎症反应,
然后选择性地破坏-细胞。这项研究的主要目标是阐明细胞
机制,负责胰腺细胞死亡,并确定机制,
保护自己免受细胞因子和自由基介导的损伤。一氧化氮是一氧化氮代谢的主要介质,
白细胞介素-1(IL-1)和干扰素-(IFN-γ)对细胞功能的抑制作用,也激活了
“恢复”途径,保护细胞免受甜菜碱介导的损伤。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了细胞对细胞因子的敏感性,
介导的损害。这项建议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
这些通路如何相互作用决定细胞命运。有三个具体目标。
1.为了验证细胞功能的不可逆抑制与细胞内的开关有关的假设,
从坏死到凋亡的死亡机制以及一氧化氮的产生速率,
NAD的细胞水平和DNA损伤的程度促成了这种机械转换。
2.为了验证一氧化氮激活细胞内AMPK以及AMPK对细胞内的细胞增殖和分化至关重要的假设,
细胞从细胞因子和一氧化氮介导的损伤中的“功能恢复”。
3.为了检验FoxO 1是控制细胞对细胞因子应答的主要调节因子的假设,
一氧化氮在细胞具有从精氨酸介导的损伤中恢复的能力的条件下,
FoxO 1指导一个转录程序,保护细胞免受氧化应激。当-细胞
FoxO 1致力于介导的死亡,它调节一个转录程序,指导细胞凋亡。
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
用于研究一氧化氮介导细胞破坏的细胞途径,
参与保护细胞免受甜菜碱介导的损伤的途径。我们希望,
从这些研究中获得了对马槟榔碱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,
disorder.
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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JOHN A CORBETT的其他文献
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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:
$ 20.37万 - 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:
$ 20.37万 - 项目类别:
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