Aging, Oxidative Stress and Cell Death
衰老、氧化应激和细胞死亡
基本信息
- 批准号:6795831
- 负责人:
- 金额:$ 124.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-09-30 至 2006-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (adapted from the application): Harman originally proposed that
cellular damage by oxygen-free radicals may be the principle driving force for
aging and substantial evidence has accumulated that suggests a major
contribution of reactive oxygen species (ROS) to the age-dependent
deteriorization of physiological functions. Because mitochondria constitute
the main site of free radical generation (and other reactive oxygen forms) in
the cell, they represent a significant and highly vulnerable target of
oxidative stress. Oxidant stress is also a well-known inducer of apoptosis,
causing programmed cell death by compromising mitochondrial structure and
function. The findings that mitochondria: a) generate reactive oxygen species;
b) are targets of oxidative stress; c) initiate oxidant-induced apoptosis; and
d) exhibit increased oxidant-induced damage with age, suggest that oxidant-induced
alterations in mitochondrial function may underlie in part the aging
phenotype. Unfortunately, the mechanisms by which oxidant stress damages
mitochondria and leads to dysfunction remain unknown. Using a variety of
transgenic mouse models coupled with new and novel optical imaging approaches,
the investigators in this proposal will test the hypothesis that oxidative
stress contributes to aging by alterations in mitochondrial structure and
function. One theory advanced to explain aging is failure of normal apoptotic
regulation, leading to accumulation of damaged cells and/or loss of
differentiated ceils. In Project 1, the hypothesis that that oxidative stress
over the lifespan of an organism, leads to failure of normal apoptotic
regulation, resulting in accelerated apoptosis contributing to aging will be
examined. Age associated increases in mtDNA deletions and other mutations,
increased oxidative damage to mtDNA and increased levels of aberrant forms of
mtDNA have all been observed. Project 2 will examine the hypothesis that
increased oxidative base damage in mtDNA leads to increased mitochondrial
dysfunction and aging. If free radical reactions are the major cause of aging,
over expression of cellular/mitochondrial antioxidants should in principle
retard aging with a concomitant increase in maximum lifespan. Project 3 will
test the hypothesis that altered steady state accumulation of oxidative damage
in mitochondria (through transgenic manipulation of mitochondrial antioxidant
levels), results in altered mitochondrial function and aging. Oxidant-induced
mitochondrial damage has been implicated in a number of age-dependent neuronal
diseases, and may involve oxidant-induced alterations in mitochondrial Ca2+
metabolism. Studies in Project 4 will examine the hypothesis that age-dependent
oxidant stress alters astrocyte mitochondrial Ca2+ signaling leading
to increased neuronal excitotoxicity and apoptosis. Lastly, two of the most
important lipid peroxides formed during oxidant stress are 4-hydroxynonenol
and malondialdehyde. Project 5 will test the hypothesis that age-related
oxidative stress damages key components of the mitochondrial respiratory chain
by oxidation of cardiolipin and by direct inhibition by 4-hydroxynonenal, a
toxic product of fatty acid oxidation.
描述(改编自应用程序):哈曼最初提出
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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BRIAN A. HERMAN其他文献
BRIAN A. HERMAN的其他文献
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{{ truncateString('BRIAN A. HERMAN', 18)}}的其他基金
ROLE OF CASPASE-2 IN OSTEOCOLAST APOPTOSIS AGE-EePENDENT OSTEOPOROSIS
CASPASE-2 在破骨细胞凋亡中的作用年龄相关性骨质疏松症
- 批准号:
7233105 - 财政年份:2006
- 资助金额:
$ 124.36万 - 项目类别:
The Mitochondrial Permeabilty Transition in Apoptosis
细胞凋亡中的线粒体通透性转变
- 批准号:
6763185 - 财政年份:2001
- 资助金额:
$ 124.36万 - 项目类别:
The Mitochondrial Permeabilty Transition in Apoptosis
细胞凋亡中的线粒体通透性转变
- 批准号:
6607261 - 财政年份:2001
- 资助金额:
$ 124.36万 - 项目类别:
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