CYCLIC ADP RIBOSE METABOLISM IN OXIDATIVE CELL DEATH
氧化性细胞死亡中的循环 ADP 核糖代谢
基本信息
- 批准号:6540072
- 负责人:
- 金额:$ 29.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1999
- 资助国家:美国
- 起止时间:1999-05-01 至 2004-01-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (Adapted from applicant's abstract): Oxidative stress, defined as
an abnormal accumulation of reactive oxygen species (ROS), disrupts normal cell
signaling pathways often resulting in cell death by apoptosis or necrosis.
Calcium signaling is involved in pathways leading to oxidant induced cell
death. In preliminary experiments, the investigator and his associates show
that oxidant induced apoptosis results in a marked elevation of cyclic
adenosine diphosphoribose (cADPR), which is a metabolite of NAD that elicits
calcium mobilization. The elevation of cADPR is due to activation of a membrane
cADPR synthase, linked to the activation of the mitochondrial permeability
transition (PT), and causally related to increases in levels of intracellular
free calcium. These data have led to the investigator's hypothesis, that cADPR
functions in a signaling pathway that is activated by oxidant stress and leads
to disruption of calcium homeostasis and to oxidant induced cell death. He will
test this hypothesis in PC12 cells, which are widely used as a model system of
neuronal cell death relating to oxidant toxicity. Studies will be conducted in
PC12 cells overexpressing Bcl-2, a potent inhibitor of the mitochondrial PT and
apoptosis, and in a control cell line containing only vector, to allow
segregation of events upstream and downstream from the effector phase of
apoptosis. The first specific aim is to identify the cADPR synthase(s)
activated by oxidant stress. A molecular genetic approach will be used to
determine if the target enzyme is one of two known cADPR synthases (CD38 or
BST-l) or a novel enzyme. According to the investigator, identification of the
synthase is a prerequisite to studies of the mechanism of oxidant induced
activation of cADPR and evaluation of the therapeutic potential of this
metabolism.
The second specific aim will establish whether cADPR formation is obligatory in
oxidant induced apoptosis and will identify specific functions of cADPR in cell
death. PC12 cells will be stably transfected with inducible sense and antisense
cDNA constructs encoding the cADPR synthase activated by oxidant stress. Enzyme
depletion and overexpression will then be used to assess the role of cADPR
synthase in the cell death pathway, as monitored by examination of specific
biochemical markers of apoptosis. The third specific aim will determine if
cADPR synthase activation is involved in initiating pathways of apoptosis
specific to ROS, or whether it results from ROS generated in the effector phase
of apoptosis. Initiators will include tumor necrosis factor alpha (TNF-(),
anti-Fas antibodies, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG),
Staurosporine, and serum withdrawal. The studies are designed to advance our
understanding of mechanisms of cell death and provide potentially new targets
for reduction of oxidant induced cell death that results from re-perfusion
injury following vascular or cerebral ischemia.
描述(改编自申请人的摘要):氧化应激,定义为
活性氧(ROS)的异常积累,破坏了正常细胞
信号通路通常导致细胞凋亡或坏死导致细胞死亡。
钙信号传导参与导致氧化剂诱导细胞的途径
死亡。在初步实验中,调查员和他的同事们表明
氧化剂诱导的凋亡导致周期性升高
腺苷二磷核糖(CADPR),这是一种引起NAD的代谢物
钙动员。 CADPR的升高是由于膜的激活
CADPR合酶,与线粒体通透性的激活有关
过渡(PT),与细胞内水平的增加有关
免费钙。这些数据导致了研究者的假设,即CADPR
在信号通路中的功能,该途径被氧化应激激活并引导
破坏钙稳态和氧化剂诱导的细胞死亡。他会的
在PC12细胞中检验此假设,该假设被广泛用作模型系统
与氧化剂毒性有关的神经元细胞死亡。研究将在
PC12细胞过表达Bcl-2,这是线粒体PT的有效抑制剂和
凋亡,仅包含载体的对照细胞系中,以允许
事件上游和下游的隔离效果阶段的隔离
凋亡。第一个具体目的是确定CADPR合酶
被氧化应激激活。分子遗传方法将用于
确定靶酶是否是两个已知的CADPR合酶之一(CD38或
BST-L)或新型酶。根据研究者的说法,
合酶是研究氧化剂诱导机理的先决条件
CADPR的激活和对此的治疗潜力的评估
代谢。
第二个具体目的将确定CADPR成立是否是强制性的
氧化剂诱导的凋亡,并将识别CADPR的特定功能
死亡。 PC12细胞将通过诱导型和反义稳定转染
cDNA构建编码由氧化剂应激激活的CADPR合酶。酶
然后,耗竭和过表达将用于评估CADPR的作用
细胞死亡途径中的合酶,通过检查特异性
凋亡的生化标志物。第三个特定目标将确定是否
CADPR合酶激活参与凋亡途径
特定于ROS,还是在效应子阶段产生的ROS引起的
凋亡。发起人将包括肿瘤坏死因子α(TNF-(),,
抗FAS抗体,N-甲基N'N'N'N'N硝基二糖苷(MNNG),
星形孢菌素和血清戒断。研究旨在推进我们的
了解细胞死亡的机制并提供潜在的新目标
为了减少氧化剂诱导的细胞死亡,这是由于重新灌注而导致的
血管或脑缺血后的损伤。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
NMR studies and semi-empirical energy calculations for cyclic ADP-ribose.
环状 ADP-核糖的 NMR 研究和半经验能量计算。
- DOI:10.1081/ncn-100105243
- 发表时间:2001
- 期刊:
- 影响因子:0
- 作者:Rutherford,TJ;Wilkie,J;Vu,CQ;Schnackerz,KD;Jacobson,MK;Gani,D
- 通讯作者:Gani,D
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MYRON K JACOBSON其他文献
MYRON K JACOBSON的其他文献
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{{ truncateString('MYRON K JACOBSON', 18)}}的其他基金
CYCLIC ADP RIBOSE METABOLISM IN OXIDATIVE CELL DEATH
氧化性细胞死亡中的循环 ADP 核糖代谢
- 批准号:
2830719 - 财政年份:1999
- 资助金额:
$ 29.98万 - 项目类别:
CYCLIC ADP RIBOSE METABOLISM IN OXIDATIVE CELL DEATH
氧化性细胞死亡中的循环 ADP 核糖代谢
- 批准号:
6351880 - 财政年份:1999
- 资助金额:
$ 29.98万 - 项目类别:
CYCLIC ADP RIBOSE METABOLISM IN OXIDATIVE CELL DEATH
氧化性细胞死亡中的循环 ADP 核糖代谢
- 批准号:
6479399 - 财政年份:1999
- 资助金额:
$ 29.98万 - 项目类别:
CYCLIC ADP RIBOSE METABOLISM IN OXIDATIVE CELL DEATH
氧化性细胞死亡中的循环 ADP 核糖代谢
- 批准号:
6151630 - 财政年份:1999
- 资助金额:
$ 29.98万 - 项目类别:
NIACIN NUTRITION, ADP-RIBOSYLATION AND CANCER SYMPOSIUM
烟酸营养、ADP-核糖化与癌症研讨会
- 批准号:
3433936 - 财政年份:1987
- 资助金额:
$ 29.98万 - 项目类别:
ALTERATION OF NAD METABOLISM BY CHEMICAL CARCINOGENS
化学致癌物改变 NAD 代谢
- 批准号:
3186350 - 财政年份:1986
- 资助金额:
$ 29.98万 - 项目类别:
ALTERATION OF NAD METABOLISM BY CHEMICAL CARCINOGENS
化学致癌物改变 NAD 代谢
- 批准号:
3186348 - 财政年份:1986
- 资助金额:
$ 29.98万 - 项目类别:
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