IRON & OXYGEN BIOLOGY IN SCH, HH & BETA-THAL MICE
铁
基本信息
- 批准号:6258562
- 负责人:
- 金额:$ 19.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-06-01 至 2003-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Patients with primary or secondary hemochromatosis are liable to cardiac and hepatic failure, and type II diabetes. Despite the (highly likely) conjecture that iron-mediated tissue damage involves the conspiracy of cellular oxidizing and reducing equivalents, the pathophysiologic events have not been fully elucidated. The present investigations represent an attempt to define the toxic effects of iron on intracellular organelles, in particular, mitochondria and lysosomes. The tissues at risk- heart, liver and pancreatic beta cells - all have highly active mitochondria which incidentally generate activated oxygen species capable of causing synergistic toxicity with intracellular iron. Our investigations center about three specific hypotheses: (1) Iron is more toxic to cells with active mitochondria. (2) The mitochondrial genome is preferentially damaged by iron-mediated oxidative reactions and accumulation of mutational events leads to mitochondrial dysfunction. (3) 'Loose' intracellular iron also causes the oxidative destabilization of lysosomes, causing leak of digestive enzymes into the cell cytoplasm and eventuating in apoptotic or necrotic cell death. These hypotheses will be tested by: (1) Determining whether cultured myeloid cells and myoblasts with active mitochondria are more readily damaged by iron loading than are cells depleted in mitochondrial function (via long-term culture in ethidium bromide or treatment with selected inhibitors). (2) Using full-length quantitative polymerase chain reaction, we will determine whether the mitochondrial genome in iron-loaded cultured myoblasts accumulates modification which prevent read-through by the polymerase compared with similar lengths of genes within the nuclear genome. In these experiments, several techniques will also be used to estimate the state of 'intactness' of cellular lysosomes. (3) Similar investigations of mitochondrial vs. nuclear DNA damage and lysosomal integrity will also be conducted on mice with congenital or acquired iron-overload, mice expressing 50 percent of normal manganese superoxide dismutase (the mitochondrial form of the enzyme), sickle hemoglobin and thalassemia. The resulting information will be used to help probe the efficiency of presently available and experimental chelators, not only in promoting iron excretion but also in the prevention of defined types of cellular damage.
原发性或继发性血色素沉着症患者容易发生心脏和肝功能衰竭,以及II型糖尿病。尽管(极有可能)推测铁介导的组织损伤涉及细胞氧化和还原当量的阴谋,但病理生理事件尚未完全阐明。目前的研究是试图确定铁对细胞内细胞器,特别是线粒体和溶酶体的毒性作用。处于危险中的组织——心脏、肝脏和胰腺细胞——都有高度活跃的线粒体,这些线粒体偶然产生的活性氧能够与细胞内的铁产生协同毒性。我们的研究主要集中在三个特定的假设上:(1)铁对线粒体活跃的细胞更有毒性。(2)线粒体基因组优先被铁介导的氧化反应损伤,突变事件的积累导致线粒体功能障碍。(3)“松散”的细胞内铁也会导致溶酶体的氧化不稳定,导致消化酶泄漏到细胞质中,最终导致细胞凋亡或坏死死亡。这些假设将通过以下方式得到验证:(1)确定培养的线粒体活跃的髓细胞和成肌细胞是否比线粒体功能衰竭的细胞更容易被铁负荷损伤(通过长期使用溴化乙啶培养或使用选定的抑制剂治疗)。(2)利用全长定量聚合酶链反应,我们将确定与核基因组中相似长度的基因相比,铁负载培养的成肌细胞线粒体基因组中是否积累了阻止聚合酶读取的修饰。在这些实验中,还将使用几种技术来估计细胞溶酶体的“完整性”状态。(3)线粒体与核DNA损伤和溶酶体完整性的类似研究也将在先天性或获得性铁过载的小鼠、表达50%正常锰超氧化物歧化酶(酶的线粒体形式)、镰状血红蛋白和地中海贫血的小鼠身上进行。由此产生的信息将用于帮助探索目前可用的和实验性螯合剂的效率,不仅在促进铁排泄方面,而且在预防特定类型的细胞损伤方面。
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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ELIZABETH C THEIL其他文献
ELIZABETH C THEIL的其他文献
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{{ truncateString('ELIZABETH C THEIL', 18)}}的其他基金
Workshop on BioIron in Thalassemia, Sickle Cell Disease and Hemochromatosis
生物铁治疗地中海贫血、镰状细胞病和血色病研讨会
- 批准号:
6702966 - 财政年份:2004
- 资助金额:
$ 19.34万 - 项目类别:
Workshop on Biolron in Thalassemia & Sickle Cell Disease
Biolron 地中海贫血研讨会
- 批准号:
6555013 - 财政年份:2002
- 资助金额:
$ 19.34万 - 项目类别:
3 DIMENSIONAL STRUCTURE OF IRE IN FERRITIN MRNA, STUDIED BY NMR SPECTROSCOPY
通过核磁共振波谱研究铁蛋白 mRNA 中 IRE 的三维结构
- 批准号:
6309021 - 财政年份:2000
- 资助金额:
$ 19.34万 - 项目类别:
Ferritin and Iron Nutrition in Health and Disease
健康和疾病中的铁蛋白和铁营养
- 批准号:
6436336 - 财政年份:1998
- 资助金额:
$ 19.34万 - 项目类别:
FERRITIN AND IRON DEFICIENCY--A NEW LOOK AT THE PROBLEM
铁蛋白和缺铁——对问题的新看法
- 批准号:
2901238 - 财政年份:1998
- 资助金额:
$ 19.34万 - 项目类别:
FERRITIN AND IRON DEFICIENCY--A NEW LOOK AT THE PROBLEM
铁蛋白和缺铁——对问题的新看法
- 批准号:
2797653 - 财政年份:1998
- 资助金额:
$ 19.34万 - 项目类别:
FERRITIN AND IRON DEFICIENCY--A NEW LOOK AT THE PROBLEM
铁蛋白和缺铁——对问题的新看法
- 批准号:
6184363 - 财政年份:1998
- 资助金额:
$ 19.34万 - 项目类别:
Ferritin and Iron Nutrition in Health and Disease
健康和疾病中的铁蛋白和铁营养
- 批准号:
6686411 - 财政年份:1998
- 资助金额:
$ 19.34万 - 项目类别:
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