MOLECULAR MECHANISMS OF CELL DEATH IN PD MITOCHONDRIA
PD 线粒体细胞死亡的分子机制
基本信息
- 批准号:6475059
- 负责人:
- 金额:$ 23.19万
- 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:2001-08-01 至 2002-07-31
- 项目状态:已结题
- 来源:
- 关键词:Parkinson's disease apoptosis cell line clinical research disease /disorder etiology disease /disorder model electron transport gene expression human genetic material tag human tissue hybrid cells membrane potentials mitochondrial DNA mitochondrial membrane mitogen activated protein kinase molecular pathology neuropathology oxidative stress postmortem protooncogene respiratory enzyme
项目摘要
Idiopathic Parkinson's disease (PD) afflicts about 1 million Americans, causes widespread suffering in the individuals, and exacts a significant economic toll on society from its production on progressive motor disability. PD symptoms arise from the premature and accelerated death of substantia nigra dopamine neurons and are commonly treated with drugs that replace dopamine synaptic function in the nigrostriatal pathway. However, no available symptomatic drugs have been shown to reduce disease progression by slowing the death of dopamine neurons in humans. Studies performed mainly by the defect in mitochondrial genes coding for complex I of the electron transport chain is responsible for increased oxidative stress, detrimental changes in intracellular calcium signaling, altered mitochondrial replication and movement, and increased susceptibility to cell death mediated by mitochondrial dysfunction. This Project is the third laboratory-based study in a four Project application for a Parkinson's Research Center of Excellence. This Project will explore the molecular mechanisms of cell death produced by PD mitochondria whose genetic functions are isolated and amplified in the cytoplasmic hybrid (cybrid) cell model developed and extensively studied by this group. Results in PD cybrids will be compared to a pharmacological model of chronic complex I impairment produced by rotenone. Four Specific Aims will be examined that test interrelated hypotheses. First, the regulation of mitochondrial membrane potential will be studied with respect to the how cyclical mitochondrial depolarization-repolarization, first described in neural cells by the PI's laboratory, is altered in PD. Second, the effects of over-expressing the anti-apoptotic proteins bcl-2 and bcl-XL on cyclical mitochondrial depolarization and reduced mitochondrial membrane potential in PD will be determined. Third, the molecular mechanisms connecting mitochondrial depolarization to activation of MAPKinase cascade will be defined in control and PD models. Fourth, properties of mitochondrial transition pore (MTP) complexes isolated from PD and control brain tissues will be characterized. These properties included the very recent finding from this group that human brain MTP complexes bind cytochrome c. Depolarization-induced release of cytochrome c and the influence of recombinant bcl proteins and BH region mutants will be studied in MTP-liposomes. This project interacts extensively with the other two laboratory projects and will develop model systems to define mechanisms of action for drugs that might be neuroprotective in PD.
特发性帕金森病(PD)困扰着大约100万美国人,在个体中引起广泛的痛苦,并且从其对进行性运动残疾的产生中对社会造成显著的经济损失。PD症状由黑质多巴胺神经元的过早和加速死亡引起,通常用替代黑质纹状体通路中多巴胺突触功能的药物治疗。然而,没有可用的对症药物已被证明可以通过减缓人类多巴胺神经元的死亡来减少疾病进展。主要通过编码电子传递链复合物I的线粒体基因的缺陷进行的研究负责增加氧化应激、细胞内钙信号传导的有害变化、改变线粒体复制和运动以及增加对线粒体功能障碍介导的细胞死亡的易感性。该项目是帕金森病卓越研究中心四个项目申请中的第三个基于实验室的研究。本项目将探索PD线粒体产生的细胞死亡的分子机制,其遗传功能在该小组开发和广泛研究的胞质杂交(cybrid)细胞模型中分离和扩增。PD胞质杂交体的结果将与鱼藤酮产生的慢性复合物I损伤的药理学模型进行比较。四个具体目标将被检查,测试相互关联的假设。首先,线粒体膜电位的调节将被研究关于如何周期性线粒体去极化-复极化,首先由PI的实验室在神经细胞中描述,在PD中改变。其次,将确定过表达抗凋亡蛋白bcl-2和bcl-XL对PD中周期性线粒体去极化和线粒体膜电位降低的影响。第三,将在对照和PD模型中定义连接线粒体去极化与MAP激酶级联激活的分子机制。第四,将表征从PD和对照脑组织分离的线粒体过渡孔(MTP)复合物的性质。这些性质包括该小组最近的发现,即人脑MTP复合物结合细胞色素c。将在MTP-脂质体中研究去极化诱导的细胞色素c释放以及重组bcl蛋白和BH区突变体的影响。该项目与其他两个实验室项目广泛互动,并将开发模型系统,以定义可能在PD中具有神经保护作用的药物的作用机制。
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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JAMES PEPPER BENNETT其他文献
JAMES PEPPER BENNETT的其他文献
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Manipulation of Mitochondrial Genomes in Aging and Neurodegeneration
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Manipulation of Mitochondrial Genomes in Aging and Neurodegeneration
衰老和神经退行性疾病中线粒体基因组的调控
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7282401 - 财政年份:2004
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$ 23.19万 - 项目类别:
Mitochondrial Genomes in Aging & Neurodegeneration
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6741600 - 财政年份:2004
- 资助金额:
$ 23.19万 - 项目类别:
MOLECULAR MECHANISMS OF CELL DEATH IN PD MITOCHONDRIA
PD 线粒体细胞死亡的分子机制
- 批准号:
6618257 - 财政年份:2002
- 资助金额:
$ 23.19万 - 项目类别:
MOLECULAR MECHANISMS OF CELL DEATH IN PD MITOCHONDRIA
PD 线粒体细胞死亡的分子机制
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6664103 - 财政年份:2002
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