DNA Mismatch Repair and Malaria Drug Resistance

DNA 错配修复和疟疾耐药性

• 批准号: 7472182
• 负责人: Theodore F Taraschi
• 金额: $ 23.16万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7472182
• 关键词: Ablation; Antimalarials; Biological Assay; Biology; Cells; Cessation of life; Characteristics; DNA; DNA Damage; DNA lesion; Development; Disease; Drug resistance; Drug-sensitive; Gene Mutation; Genome; Genomics; Health; Homologous Gene; Human; In Vitro; Link; MSH3 gene; Malaria; Malignant Neoplasms; Microsatellite Instability; Mismatch Repair; Multi-Drug Resistance; Nuclear; Parasites; Pathway interactions; Pharmaceutical Preparations; Phenotype; Plasmodium; Plasmodium falciparum; Play; Population; Public Health; Resistance; Role; chemotherapy; repaired

DESCRIPTION (provided by applicant): The inability of cells to maintain genomic integrity leads to the rapid accumulation of DNA mutations, a scenario that underlies many diseases. In particular, the ablation of DNA mismatch repair (MMR) activity has been linked to several forms of cancer, microsatellite instability, and most notably chemotherapeutic drug resistance. DNA damaging agents used as drug treatments are often associated with a resistance phenotype in cells with decreased MMR activity. Many of the most commonly used antimalarial drugs are DNA altering agents and may play a critical role in the selection of a drug resistant phenotype within the malaria parasite. This resistance may be directly associated with a loss or decrease of MMR activity within parasites. Given Plasmodium falciparum's rapid development of drug resistance and its unusually high A-T rich genome, characteristic of a mutator phenotype, it is not difficult to imagine that the parasite has greatly diminished post-replication repair efficiency. Moreover, the absence of an MSH3 and MSH5 homologue from the Plasmodium genome may allow the persistence of certain types of DNA lesions that would otherwise be removed by the MMR pathway. It is our hypothesis that P. falciparum drug resistant strains have decreased repair of mispaired DNA substrates and that this decreased activity is the underlying mechanism in the development of malaria drug resistance. Efficient MMR plays an indispensable role in determining cellular sensitivity to DNA altering agents. We further hypothesize that current antimalarial drugs, some of which are known DNA altering agents, are selecting for a population of parasites possessing a decreased MMR efficiency. Therefore, we propose to investigate the role that MMR plays in Plasmodium falciparum drug resistance. PUBLIC HEALTH RELEVANCE Human malaria is an enormous global health problem, infecting 300-500 million people, and causing 1-3 million deaths annually. Understanding how Plasmodium falciparum maintains genomic integrity is uncharted territory within malaria biology and may be the key to elucidating the parasites extraordinary adaptability to chemotherapy. It is our hypothesis that P. falciparum drug resistant strains have decreased repair of mispaired DNA substrates and that this decreased activity is the underlying mechanism in the development of malaria drug resistance.

描述（由申请人提供）：细胞维持基因组完整性的无能导致DNA突变的迅速积累，DNA突变是许多疾病基础的情况。特别是，DNA不匹配修复（MMR）活性的消融与几种形式的癌症，微卫星不稳定性以及最著名的化学治疗耐药性有关。用作药物治疗的DNA损伤剂通常与MMR活性降低的细胞中的抗性表型有关。许多最常用的抗疟药是DNA改变剂，并且可能在疟原虫寄生虫内的耐药表型中起关键作用。这种电阻可能与寄生虫中MMR活性的损失或减少有关。鉴于恶性疟原虫的耐药性快速发展及其异常高的A-T富集基因组，这是突变体表型的特征，因此不难想象寄生虫大大降低了复制后修复效率。此外，从疟原虫基因组中缺乏MSH3和MSH5同源物可能会允许某些类型的DNA病变的持久性，否则MMR途径将去除这些病变。我们的假设是，恶性疟原虫抗药性菌株的修复降低了，DNA底物的修复程度降低，而这种降低的活性是疟疾耐药性发展的基本机制。有效的MMR在确定细胞敏感性对DNA改变剂的敏感性中起着必不可少的作用。我们进一步假设，当前的抗疟药（其中一些是已知的DNA改变剂）正在选择具有MMR效率降低的寄生虫种群。因此，我们建议研究MMR在恶性疟原虫耐药性中的作用。公共卫生相关性人类疟疾是一个巨大的全球健康问题，感染了300-5亿人，每年造成1-3万人死亡。了解恶性疟原虫在疟疾生物学中如何保持基因组完整性是未知的领域，并且可能是阐明寄生虫对化学疗法的非凡适应性的关键。我们的假设是，恶性疟原虫抗药性菌株的修复降低了，DNA底物的修复程度降低，而这种降低的活性是疟疾耐药性发展的基本机制。