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:6479399
- 负责人:
- 金额:$ 16.58万
- 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 2003-01-31
- 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(改编自申请人摘要):氧化应激,定义为
活性氧(ROS)的异常积累,破坏正常细胞
信号通路通常导致细胞凋亡或坏死而死亡。
钙信号参与氧化诱导细胞凋亡的途径
死亡在初步的实验中,研究人员和他的同事表明,
氧化剂诱导的细胞凋亡导致细胞周期的显著升高,
腺苷二磷酸核糖(cADPR),是NAD的代谢产物,
钙动员cADPR的升高是由于细胞膜的激活,
cADPR合酶,与线粒体通透性的激活有关
过渡(PT),并与细胞内
游离钙这些数据导致了研究者的假设,即cADPR
在氧化应激激活的信号通路中起作用,
钙稳态的破坏和氧化剂诱导的细胞死亡。他将
在PC 12细胞中测试这一假设,PC 12细胞被广泛用作
与氧化剂毒性有关的神经元细胞死亡。研究将在
过表达Bcl-2(一种有效的线粒体PT抑制剂)的PC 12细胞,
在仅含有载体的对照细胞系中,
分离的事件上游和下游的效应阶段,
凋亡第一个具体目标是鉴定cADPR合酶
被氧化应激激活将使用分子遗传学方法来
确定靶酶是否是两种已知的cADPR转移酶(CD 38或
BST-1)或新的酶。据调查人员称,
合成酶是研究氧化剂诱导细胞凋亡机制的前提
cADPR的激活和评估其治疗潜力
新陈代谢.
第二个具体目标是确定cADPR的形成是否是强制性的,
氧化剂诱导细胞凋亡,并将确定cADPR在细胞中的特定功能
死亡PC 12细胞将用诱导型正义和反义寡核苷酸稳定转染。
编码由氧化应激激活的cADPR合酶的cDNA构建体。酶
然后将使用cADPR的缺失和过表达来评估cADPR的作用。
合成酶在细胞死亡途径中的作用,如通过检查特异性
凋亡的生化标志物。第三个具体目标将决定,
cADPR合酶激活参与启动细胞凋亡途径
特异于ROS,或者是否由效应期产生的ROS引起
细胞凋亡。启动剂将包括肿瘤坏死因子α(TNF-α),
抗Fas抗体,N-甲基-N ′-硝基-N-亚硝基胍(MNNG),
星形孢菌素和血清戒断。这些研究旨在推动我们的
了解细胞死亡的机制,并提供潜在的新靶点
用于减少由再灌注引起的氧化剂诱导的细胞死亡
血管或脑缺血后的损伤。
项目成果
期刊论文数量(0)
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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:
$ 16.58万 - 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:
6540072 - 财政年份:1999
- 资助金额:
$ 16.58万 - 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:
$ 16.58万 - 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:
$ 16.58万 - 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:
$ 16.58万 - 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:
$ 16.58万 - 项目类别:
ALTERATION OF NAD METABOLISM BY CHEMICAL CARCINOGENS
化学致癌物改变 NAD 代谢
- 批准号:
3186346 - 财政年份:1986
- 资助金额:
$ 16.58万 - 项目类别: