CARDIOPROTECTIVE EFFECT--NEW CHELATORS FOR THALASSEMIA
心脏保护作用--地中海贫血新螯合剂
基本信息
- 批准号:2840963
- 负责人:
- 金额:$ 11.01万
- 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:1999-06-01 至 2002-05-31
- 项目状态:已结题
- 来源:
- 关键词:ascorbate chelating agents chelation therapy cytoprotection disease /disorder model drug interactions drug screening /evaluation electrophysiology endoplasmic reticulum enzyme activity ethylenediamines heart cell heart metabolism heart pharmacology hydropathy iron storage disorder laboratory rat liver cirrhosis liver metabolism myocardium nonhuman therapy evaluation prodrugs respiratory enzyme thalassemia tissue /cell culture
项目摘要
Research on the pathogenesis of myocardial iron toxicity, the most critical life-limiting complication of thalassemic iron overload, has been seriously hindered by failure to develop an animal model simulating transfusional siderosis. Consequently, we have developed a system of cultured rat cardiomyocytes in which iron-loading with non-transferrin iron results in structural and functional abnormalities analogous with hemosiderotic myocardiopathy. In the present proposal we wish to test the hypothesis that (a) depletion of the chelatable cellular labile iron pool may permit recovery of heart cell function, documented by reversal of the iron-induced abnormalities in contractility and rhythmicity, increased lipid peroxidation, loss of sarcolemmal thiolic proteins, increased lysosomal fragility and abnormal mitochondrial respiratory function (b) that hexadentate chelators offer a predictable protective effect whereas tridentate and bidentate chelators (such as L1) may cause internal iron redistribution and a paradoxical enhancement of the harmful Fenton reaction and; (c) that lipophilic chelators are more efficient in penetrating heart cells allowing reversal of existing damage whereas hydrophilic chelators may have superior ability to prevent iron-induced damage. Hypertransfused rats with selective radioiron probes of hepatocellular and reticuloendothelial iron stores will be used to define the pools of iron available for in vivo mobilization. The ability of ascorbate to enhance chelating efficiency and of alpha-tocopherol to prevent peroxidative damage will be explored in both experimental systems. The proposed studies represent an essential link between the pharmacologic chemistry and potential clinical application of new iron chelators by allowing insight into their mechanism of action and cardioprotective effect, providing vital informal for the development of new strategies for the management of iron overload in thalassemic patients.
心肌铁中毒是地中海贫血铁超载最严重的危及生命的并发症,由于未能建立模拟输注性铁中毒的动物模型,对心肌铁中毒发病机制的研究受到严重阻碍。因此,我们开发了一种培养大鼠心肌细胞系统,其中铁负载非转铁蛋白铁导致结构和功能异常,类似于含铁血黄素性心肌病。在目前的提议中,我们希望验证以下假设:(a)可螯合细胞不稳定铁池的消耗可能允许心脏细胞功能的恢复,通过铁诱导的收缩性和节律性异常的逆转,脂质过氧化的增加,肌层硫蛋白的损失,增加溶酶体脆性和线粒体呼吸功能异常(b)六齿螯合剂提供可预测的保护作用,而三齿和双齿螯合剂(如L1)可能导致内部铁重新分配和有害的芬顿反应的矛盾增强;(c)亲脂螯合剂更有效地穿透心脏细胞,从而逆转现有的损伤,而亲水螯合剂可能具有更好的防止铁诱导损伤的能力。高输血大鼠肝细胞和网状内皮铁储存的选择性放射性铁探针将用于确定可用于体内动员的铁池。抗坏血酸提高螯合效率的能力和α -生育酚防止过氧化损伤的能力将在两个实验系统中进行探讨。提出的研究通过深入了解新型铁螯合剂的作用机制和心脏保护作用,代表了新型铁螯合剂的药理学化学和潜在临床应用之间的重要联系,为地中海贫血患者铁超载管理的新策略的发展提供了重要的信息。
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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CHAIM HERSHKO其他文献
CHAIM HERSHKO的其他文献
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{{ truncateString('CHAIM HERSHKO', 18)}}的其他基金
CARDIOPROTECTIVE EFFECT--NEW CHELATORS FOR THALASSEMIA
心脏保护作用--地中海贫血新螯合剂
- 批准号:
6381175 - 财政年份:1999
- 资助金额:
$ 11.01万 - 项目类别:
CARDIOPROTECTIVE EFFECT--NEW CHELATORS FOR THALASSEMIA
心脏保护作用--地中海贫血新螯合剂
- 批准号:
6177862 - 财政年份:1999
- 资助金额:
$ 11.01万 - 项目类别:
CARDIAC MYOCYTES CULTURED BEATING--IRON OVERLOAD MODEL
心肌细胞培养跳动--铁超载模型
- 批准号:
2148161 - 财政年份:1986
- 资助金额:
$ 11.01万 - 项目类别:
CULTURED CARDIAC MYOCYTES--A MODEL OF IRON OVERLOAD
培养的心肌细胞——铁过量的模型
- 批准号:
3346632 - 财政年份:1986
- 资助金额:
$ 11.01万 - 项目类别:
CULTURED CARDIAC MYOCYTES--A MODEL OF IRON OVERLOAD
培养的心肌细胞——铁过量的模型
- 批准号:
3346635 - 财政年份:1986
- 资助金额:
$ 11.01万 - 项目类别:
CULTURED CARDIAC MYOCYTES--A MODEL OF IRON OVERLOAD
培养的心肌细胞——铁过量的模型
- 批准号:
3346636 - 财政年份:1986
- 资助金额:
$ 11.01万 - 项目类别:
CARDIAC MYOCYTES CULTURED BEATING--IRON OVERLOAD MODEL
心肌细胞培养跳动--铁超载模型
- 批准号:
2148160 - 财政年份:1986
- 资助金额:
$ 11.01万 - 项目类别:
CARDIAC MYOCYTES CULTURED BEATING--IRON OVERLOAD MODEL
心肌细胞培养跳动--铁超载模型
- 批准号:
2148162 - 财政年份:1986
- 资助金额:
$ 11.01万 - 项目类别:
CULTURED CARDIAC MYOCYTES--A MODEL OF IRON OVERLOAD
培养的心肌细胞——铁过量的模型
- 批准号:
3346637 - 财政年份:1986
- 资助金额:
$ 11.01万 - 项目类别:
CULTURED CARDIAC MYOCYTES--A MODEL OF IRON OVERLOAD
培养的心肌细胞——铁过量的模型
- 批准号:
3346633 - 财政年份:1986
- 资助金额:
$ 11.01万 - 项目类别:
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