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UBIQUINONE AND MITOCHONDRIAL OXIDATIVE DISORDERS OF AGIN

AGIN 的泛醌和线粒体氧化障碍

基本信息

批准号：
6606132
负责人：
Manuchair Ebadi
金额：
$ 35.04万
依托单位：
UNIVERSITY OF NORTH DAKOTA
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：
1999-07-16 至 2006-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6606132
关键词：
actins adenosine triphosphate aging antioxidants apoptosis brain metabolism laboratory mouse laboratory rat mitochondria neural degeneration neurofilament neuroprotectants oxidative stress pharmacokinetics superoxide dismutase ubiquinone

项目摘要

DESCRIPTION: (Verbatim from the Applicant's Abstract) The long-term objective of the proposal is to clarify the mechanism of mitochondrial-linked apoptosis associated with aging and neurodegenerative disorders. Human mitochondrial DNA(mtDNA) deletion mutations have been found in a number of neurodegenerative diseases, including Kearns-Sayre syndrome, Leber's hereditary optic neuropathy, Alzheimer's disease, and Parkinson's disease, and with aging. Abnormalities in mitochondrial metabolism likewise have been associated with neurodegenerative disease, e.g., Huntington's disease. In addition, a decline of aerobic energy metabolism in the affected tissue is often associated with the progression of these neurodegenerative diseases. A decline in aerobic metabolism has been observed in aging tissues. Ubiquinone(coenzyme Q10), in addition to its function as an electron and proton carrier in mitochondrial electron transport coupled to ATP synthesis, acts in its reduced form(ubiqionol) as an antioxidant, inhibiting lipid peroxidation in biological membranes and protecting mitochondrial inner-membrane proteins and DNA against oxidative damage accompanying lipid peroxidation. Ubiquinol is the only known lipid-soluble antioxidant that animal cells can synthesize de novo and for which there exists enzymic mechanisms which can regenerate it from its oxidized product formed in the course of its antioxidant function. Tissue ubiqionone levels are subject to regulation by physiological factors that are related to the oxidative activity of the organism: they increase under the influence of oxidative stress, e.g. physical exercise, cold adaptation, thyroid hormone treatment, and decrease during aging. The specific aims of this proposal are: A) to ascertain the natural distribution and comprehensive pharmacokinetic parameters of ubiquinone(coenzyme Q10) and its regional distribution in the CNS; B) to search for one of the molecular links to neurodegeneration by studying the interaction among ubiquitin, ATP-dependent pathways, G actin, and neurofilaments in neurons; C) to test the effects of neuroprotectants such as selegiline on the striatal-, hippocampal-, and cortical levels of coenzyme Q10; D) to explore the antioxidant coregulation governing the status of Mn++ superoxide dismutase found in the mitochondria, Cu++, Zn++ superoxide dismutase located in the cytoplasm; and coenzyme Q10 found both in the mitochondria and cytoplasm; and E) to learn whether or not the administration of coenzyme Q10 could protect glial elements and neurons against neurotoxins such as MPTP causing Parkinsonism or NMDA- and non NMDA receptor activation causing excitatoxic disruption of Ca++ homeostasis and ensuing oxidative stress. The completion of these studies will undoubtedly provide additional items of information on reactive oxygen species-induced damage of mitochondrial DNA and the protective effects of coenzyme Q10(ubiquinol) to minimize it.

描述：（申请人摘要中的逐字记录）长期目标这一建议的目的是阐明神经细胞凋亡的机制，与衰老和神经退行性疾病有关。人线粒体 DNA（线粒体DNA）缺失突变已在许多神经退行性疾病中发现疾病，包括Kearns-Sayre综合征，Leber遗传性视神经病变，老年痴呆症，帕金森症，以及衰老。异常线粒体代谢同样与神经退行性疾病有关，疾病，例如，亨廷顿氏病。此外，有氧能量的下降受影响组织中的代谢通常与这些神经退行性疾病。有氧代谢的下降在老化组织中观察到。泛醌（辅酶Q10），除了其在线粒体电子传递中作为电子和质子载体发挥作用与ATP合成偶联，以其还原形式（泛醇）作为抗氧化剂，抑制生物膜中的脂质过氧化，保护线粒体内膜蛋白和DNA免受氧化损伤伴随脂质过氧化的损害。泛醌醇是唯一已知的脂溶性抗氧化剂，动物细胞可以从头合成和形成存在酶机制，可以使其从氧化的产品在其抗氧化功能的过程中形成。组织泛酮水平受生理因素的调节，生物体的氧化活性：它们在以下因素的影响下增加：氧化应激，例如体育锻炼、冷适应、甲状腺激素治疗，并在老化过程中减少。这项建议的具体目标是： A）确定自然分布和综合药代动力学泛醌（辅酶Q10）的参数及其区域分布 CNS; B）通过以下途径寻找与神经变性的分子联系之一：研究泛素，ATP依赖途径，G肌动蛋白， C）测试神经保护剂的作用，如司来吉兰对纹状体、海马和皮质辅酶Q10水平的影响; D）探讨Mn ~（++）状态的抗氧化协同调节超氧化物歧化酶存在于线粒体中，Cu++、Zn++超氧化物歧化酶位于细胞质中;辅酶Q10存在于线粒体中， E）了解是否给予辅酶Q10 可以保护神经胶质细胞和神经元免受神经毒素如MPTP 引起帕金森综合征或NMDA和非NMDA受体激活，兴奋毒性破坏Ca++稳态和随后的氧化应激。的这些研究的完成无疑将提供更多的项目，活性氧引起线粒体DNA损伤的信息，辅酶Q10（泛醇）的保护作用，以尽量减少它。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Complex-1 activity and 18F-DOPA uptake in genetically engineered mouse model of Parkinson's disease and the neuroprotective role of coenzyme Q10.

帕金森病基因工程小鼠模型中 Complex-1 活性和 18F-DOPA 摄取以及辅酶 Q10 的神经保护作用。

DOI：
10.1016/j.brainresbull.2005.11.019
发表时间：
2006
期刊：
Brain research bulletin
影响因子：
3.8
作者：
Sharma,SushilK;ElRefaey,Hesham;Ebadi,Manuchair
通讯作者：
Ebadi,Manuchair

Introduction. Oxidative stress in mitochondria disorders of aging.

介绍。

DOI：
10.1159/000046872
发表时间：
2001
期刊：
Biological signals and receptors
影响因子：
0
作者：
Ebadi,M
通讯作者：
Ebadi,M

1-Methyl-4-phenyl-pyridinium ion-induced oxidative stress, c-Jun phosphorylation and DNA fragmentation factor-45 cleavage in SK-N-SH cells are averted by selegiline.

司来吉兰可避免 SK-N-SH 细胞中 1-甲基-4-苯基-吡啶鎓离子诱导的氧化应激、c-Jun 磷酸化和 DNA 片段化因子 45 裂解。

DOI：
10.1016/j.neuint.2008.08.007
发表时间：
2008
期刊：
Neurochemistry international
影响因子：
4.2
作者：
Chetsawang,Banthit;Kooncumchoo,Patcharee;Govitrapong,Piyarat;Ebadi,Manuchair
通讯作者：
Ebadi,Manuchair

Ubiquinone (coenzyme Q10) and complex I in mitochondrial oxidative disorder of Parkinson's disease.

泛醌（辅酶 Q10）和复合物 I 在帕金森病线粒体氧化紊乱中的作用。