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
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:
3186348 - 财政年份:1986
- 资助金额:
$ 16.58万 - 项目类别:














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