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HEMOGLOBIN MEDIATED DAMAGE IN THALASSEMIC ERYTHROCYTES

血红蛋白介导的地中海贫血红细胞损伤

基本信息

批准号：
2460080
负责人：
MARK D SCOTT
金额：
$ 21.49万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-08-01 至 1999-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2460080
关键词：
antioxidants autooxidation cellular pathology chelating agents cofactor enzyme mechanism erythrocytes free radical oxygen heme hemoglobin hemoglobin As hemoprotein structure human subject iron metabolism porphyrin biosynthesis protein degradation thalassemia

项目摘要

The thalassemias arise from unbalanced globin chain synthesis due to deletions of, or mutations to, the Beta- and alpha-hemoglobin genes. As a consequence, unpaired alpha- or Beta-hemoglobin chains (alpha- and Beta-chains) are present within the thalassemic red blood cell (RBC). These unpaired chains are thought to contribute to the ineffective erythropoiesis and shortened RBC survival noted in the thalassemias. Surprisingly, while the RBC abnormalities in thalassemic are well characterized, little is known of the mechanisms by which unpaired alpha- and Beta-chains injure the cell. Our lack of knowledge regarding the cellular pathology of the thalassemic cell is due to: 1) the onset and development of cellular pathology occur quite rapidly in vivo; and 2) the most severely affected RBC are swiftly destroyed in either the bone marrow or in the peripheral blood. Consequently, it has not been possible to directly investigate the mechanism by which unpaired alpha- and Beta-chains damage the RBC. To circumvent these problems, I have developed models of the alpha and Beta thalassemic RBC. These model cells, made by entrapment of purified alpha- and Beta-chains in normal RBC, develop functional and structural changes almost identical to those seen in thalassemic patient RBC. Using the model thalassemic RBC, in conjunction with patient samples, it is now possible to experimentally examine the mechanisms by which unpaired hemoglobin chains mediate cell damage. Importantly, the model thalassemic cells also provide a unique means to experimentally evaluate possible therapeutic agents. It is the hypothesis of this proposal that the inherent instability of the unpaired globin chains results in the generation of reactive oxygen species and the release of globin free heme and iron and that these agents underlie the pathophysiology of the thalassemic RBC. Furthermore, by determining the direct mechanisms by which unpaired globin chains injure the RBC, therapeutic interventions can be designed that prevent cell damage. Based on these hypotheses, the specific aims of the research proposal are to: A) elucidate the direct mechanisms by which heme and iron are released from unpaired alpha- and Beta-chains; B) determine the fate of the globin derived heme and iron and, subsequently, identify the specific sites, mechanisms, and pathological consequences of damage to the RBC; and C) evaluate interventions (e.g., antioxidants and chelators) that diminish or block damage by unpaired alpha- and Beta-chains. The results of these studies will provide significant new insights into the pathophysiology of the thalassemic cell and give experimental evidence for therapeutic agents that might improve in vivo erythropoiesis and RBC survival.

地中海贫血是由不平衡的珠蛋白链合成引起的， β和α血红蛋白基因的缺失或突变。作为结果，不成对的α-或β-血红蛋白链（α-和β-血红蛋白链） β链）存在于地中海贫血红细胞（RBC）中。这些不成对的链被认为是导致无效的红细胞生成和缩短的红细胞存活率。令人惊讶的是，虽然地中海贫血患者的红细胞异常特征，很少有人知道的机制，不成对的α- 而β-链会伤害细胞。我们缺乏知识，地中海贫血细胞的细胞病理学是由于：1）发病和细胞病理学的发展在体内发生得相当快;和2）大多数严重受影响的红细胞在骨骼中迅速被破坏，骨髓或外周血中。因此，可以直接研究未配对的α- 而β链会破坏红细胞为了解决这些问题，我开发了α和β地中海贫血红细胞模型。这些模型细胞，通过将纯化的α-和β-链包埋在正常的红细胞，发展功能和结构变化几乎相同的那些在地中海贫血患者的红细胞中可见。使用地中海贫血RBC模型，结合患者样本，现在可以通过实验研究未配对血红蛋白链介导细胞凋亡的机制，损害重要的是，模型地中海贫血细胞还提供了独特的是指通过实验评估可能的治疗剂。是这一建议的假设，即不成对的固有的不稳定性球蛋白链导致活性氧物质的产生，释放的球蛋白自由血红素和铁，这些代理人的基础地中海贫血红细胞的病理生理学此外，通过确定未配对的珠蛋白链损伤RBC的直接机制，可以设计预防细胞损伤的治疗干预。基于这些假设，研究提案的具体目标是 A）阐明血红素和铁是从未配对的α-和β-链释放; B）决定球蛋白衍生的血红素和铁，随后，确定具体的红细胞损伤的部位、机制和病理后果; 和C）评估干预措施（例如，抗氧化剂和螯合剂），减少或阻止不成对的α链和β链造成的损害。结果这些研究将提供重要的新见解，地中海贫血细胞的病理生理学，并给出实验证据对于可能改善体内红细胞生成和RBC的治疗剂，生存