RESISTANT (MDR) GENE IN RODENT MALARIA

本项目的长期目标是阐明药物的作用机制 特别是疟原虫的耐药性，以确定 多药耐药基因（MDR）。 这一课题意义重大 考虑到疟疾治疗的惊人增加， 由于耐药性而导致的失败。 尽管规模的 问题是寄生虫对大多数 人们对抗疟疾药物的了解不清楚。 更好地了解 这些机制将导致新的控制战略， 疾病 在恶性疟原虫中发现了两个mdr样基因， 其中pfmdf 1基因与耐药性有关， 表型。 然而，在以下方面仍存在重大争议： pfmdr基因与氯喹耐药性的关系。 假单 恶性疟原虫模型对于研究这些作用具有重要的局限性， 基因，例如，只有红细胞阶段可以在体外维持 而合适的动物模型，黑猩猩，是昂贵的， 不切实际 在体内使用啮齿类疟疾克隆（伯氏疟原虫和伯氏疟原虫）， yoeli），表达不同的药物敏感性模式，提供了一种 这是研究这种表型的分子机制的极好模型。 在 在本建议中，我们将集中精力确定以下方面的作用： 小鼠多药耐药基因在疟疾耐药中的作用。 我们有 结果表明，在伯氏疟原虫中存在mdr-like基因，并可能存在于伯氏疟原虫中。 yoelii。 为了确定伯氏疟原虫和约氏疟原虫的mdr-homolgues 在寄生虫抗药性中发挥作用，我们将分析 这些基因在DNA、RNA、蛋白质和染色体水平上与五种P. berghei衍生系和四个约氏疟原虫17 X衍生系， 不同的耐药性模式。

The long term goal of our project is to elucidate the mechanism(s) of drug resistance in Plasmodium spp, particularly, to determine the role played by the multidrug resistance genes (mdr). This subject is of immense biomedical relevance considering the alarming increase in malaria treatment failures resulting from drug resistance. Despite the magnitude of the problem the mechanism(s) of parasite resistance to the majority of antimalarial drugs are not clearly understood. A better understanding of these mechanism(s) would lead to new strategies for the control of the disease. Two mdr-like genes have been identified in P. falciparum, and one of them, the pfmdf1 gene, has been associated with the drug resistance phenotype. However, there is still significant controversy with regard to athe involvement of the pfmdr genes in chloroquine resistance. The P. falciparum model has important limitations for studying the role of these genes, for example only erythrocytic stages could be maintained in vitro and the appropriate animal model, the chimpanzee, is expensive and impractical. The use of rodent malaria clones in vivo (P. berghei and P. yoeli), expressing different patterns of drug sensitivity, provides an excellent model to study the molecular mechanisms of this phenotype. In the present proposal, we will focus our efforts to ascertain the role of the murine multidrug resistance genes in malaria drug resistance. We have shown that mdr-like genes are present in P. berghei and probably, P. yoelii. To determine whether the P. berghei and p. yoelii mdr-homolgues play a role in parasite drug resistance, we will analyze the behavior of these genes at the DNA, RNA, protein and chromosomal level in five P. berghei derived lines and four P. yoelii 17X derived lines expressing different patterns of drug resistance.