Role of Translesional Polymerases in Genome Diversification of the Malaria Parasite

跨病灶聚合酶在疟原虫基因组多样化中的作用

• 批准号: 10399466
• 负责人: Laura Kirkman
• 金额: $ 58.58万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10399466
• 关键词: Address; Affect; Africa South of the Sahara; Alleles; Animal Model; Antigen Targeting; Antigenic Diversity; Antigenic Variation; Antimalarials; Automobile Driving; Biological Models; Biology; Birds; CRISPR/Cas technology; Child; Clinical; DNA; DNA Damage; DNA Repair; DNA Sequence Alteration; DNA biosynthesis; DNA-Directed DNA Polymerase; Disease; Drug Targeting; Drug resistance; Erythrocytes; Eukaryota; Event; Exposure to; Gene Family; Generations; Genes; Genetic; Genetic Polymorphism; Genetic Recombination; Genetic Variation; Genome; Genotoxic Stress; Goals; Human; Immune response; Immune system; Individual; Infection; Knock-out; Lead; Maintenance; Malaria; Mammals; Measures; Morbidity - disease rate; Mutagenesis; Mutation; Parasites; Pathogenesis; Pathway interactions; Persons; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Play; Polymerase; Population; Primates; Process; Proteins; Reptiles; Research; Resistance development; Risk; Rodent; Role; Sequence Homologs; Surface Antigens; Techniques; Testing; Vaccines; Variant; Virulent; Widespread Disease; base; chronic infection; design; drug development; enzyme pathway; genome editing; genome sequencing; genome-wide; homologous recombination; member; mortality; neglect; novel; parasite genome; radiation response; repaired; rodent genome; single molecule real time sequencing; trait; vaccine development; whole genome

Project Summary/Abstract: Malaria continues to be a major cause of morbidity and mortality among people living in the tropical and subtropical regions of the world. The ability of parasites to continuously generate sequence diversity within their genomes is a major contributor to the inability to develop effective erythrocytic stage vaccines and to the ever-present problem of drug resistance. Yet, key gaps remain in our understanding of how the parasite genome is maintained. Our long-term goal is to identify pathways that are crucial to maintaining the parasite genome and understand how these repair pathways impact mutability and genome plasticity. Translesion (TLS) polymerases are specialized DNA polymerases that are capable of continuing DNA synthesis through damage bases and difficult templates, though they accomplish this in an error prone manner. In model systems, TLS polymerases generate the majority of novel mutations. There are only two TLS polymerase present in the primate malaria genomes, Rev 1 and pol ζ. Our hypothesis is that these polymerases play a crucial role in parasite genome maintenance and contribute to persistence of and pathogenesis of malaria by a) driving the generation of antigenic diversity by promoting homologous recombination (HR) between semi-homologous but non-identical members of multicopy gene families and b) contributing to the generation of sequence variation throughout the genome and in turn to the development of drug resistance. Using genome editing techniques, mutagenesis and SMRT sequencing techniques, we seek to uncover the role of TLS polymerases in the human malaria parasite, Plasmodium falciparum. Our proposed research will uncover unique aspects of Plasmodium DNA repair that will be important for understanding malaria and to those that study genome maintenance in general. Our aims are designed to have direct impact on the important clinical aspects of malaria, the parasite's propensity to develop drug resistance and evade the host immune system. This study addresses an important and neglected aspect of parasite biology.

项目概要/摘要： 疟疾仍然是生活在热带和亚热带地区的人发病和死亡的一个主要原因， 世界上的亚热带地区。寄生虫持续产生序列多样性的能力 是不能发展有效红细胞期的主要原因 疫苗和一直存在的耐药性问题。然而，在我们的国家， 了解寄生虫基因组是如何维持的。我们的长期目标是找出 这对维持寄生虫基因组至关重要，并了解这些修复途径如何影响 突变性和基因组可塑性。 翻译（TLS）聚合酶是能够使DNA连续化的专门的DNA聚合酶。 通过损坏的基地和困难的模板合成，虽然他们完成这一点在一个错误的倾向 方式在模型系统中，TLS聚合酶产生大多数新突变。只有 灵长类疟疾基因组中存在两种TLS聚合酶，Rev 1和pol ζ。我们的假设是 这些聚合酶在寄生虫基因组维持中起着至关重要的作用， a）通过促进抗原多样性的产生来驱动抗原多样性的产生 多拷贝半同源但不相同的成员之间的同源重组（HR） 基因家族和B）在整个基因组中和在 转向抗药性的发展。使用基因组编辑技术，诱变和SMRT 测序技术，我们试图揭示TLS聚合酶在人类疟疾中的作用， 恶性疟原虫 我们提出的研究将揭示疟原虫DNA修复的独特方面，这对 了解疟疾和那些研究基因组维持的人。我们的目标是 对疟疾的重要临床方面产生直接影响， 耐药性和逃避宿主免疫系统。这项研究解决了一个重要的和被忽视的 寄生虫生物学的一个方面。