RESISTANT (MDR) GENE IN RODENT MALARIA

我们项目的长期目标是阐明药物的作用机制(S) 尤其是要确定疟原虫在抗药性中所起的作用 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长，生物医学的相关性 由于抗药性导致的失败。尽管其规模之大 问题：寄生虫对大多数人的抗性机制(S) 抗疟疾药物还不是很清楚。更好地理解 这些机制(S)将导致新的战略控制 疾病。已在恶性疟原虫中发现两个MDR样基因，一个 其中pfmdf1基因与耐药有关。 表型。然而，关于以下方面仍然存在重大争议 Pfmdr基因与氯喹抗性的关系。通过对P. 恶性疟模型对于研究这些因素的作用有重要的局限性。 基因，例如，只有红细胞期才能在体外保持 而合适的动物模型，黑猩猩，是昂贵的和 不切实际。在体内使用啮齿动物疟疾克隆(P.berghei和P. Yoeli)，表达不同的药物敏感性模式，提供了一种 这是研究这一表型分子机制的极佳模型。在……里面 在目前的提案中，我们将集中努力确定 小鼠多药耐药基因在疟疾耐药性中的作用。我们有 结果表明，伯氏肺孢子虫和P.berghei可能存在MDR样基因。 尤利耶。以确定伯氏疟原虫和约氏疟原虫是否存在同种耐药现象 在寄生虫耐药性中发挥作用，我们将分析其行为 这些基因分别在DNA、RNA、蛋白质和染色体水平上。 Berghei派生系和4个约氏P.yoelii 17x派生系表达 不同的耐药模式。

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.