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

基本信息

批准号：
10840645
负责人：
Laura Kirkman
金额：
$ 8.29万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10840645
关键词：
Address Affect Africa South of the Sahara Alleles 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 Enzymes 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 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 acquired drug resistance base chronic infection design drug resistance development genome editing genome sequencing genome-wide homologous recombination member model organism mortality neglect novel parasite genome radiation response repaired rodent genome single molecule real time sequencing trait vaccine development whole genome

项目摘要

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.

项目摘要/摘要：疟疾仍然是居住在热带和世界亚热带地区。寄生虫连续产生序列多样性的能力在其基因组中是无法发展有效的红细胞阶段的主要贡献者疫苗和耐药性的存在问题。但是，关键差距仍然存在了解如何保持寄生虫基因组。我们的长期目标是确定途径对于维持寄生虫基因组和了解这些修复途径的影响至关重要可突变性和基因组可塑性。转化（TLS）聚合酶是能够继续DNA的专用DNA聚合酶通过损坏基础和困难模板的综合方式。在模型系统中，TLS聚合酶会产生大多数新型突变。只有灵长类动物疟疾基因组中存在两个TLS聚合酶，Rev 1和Polζ。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，并有助于持续和疟疾的发病机理a）通过促进驱动抗原多样性的产生综合副本的半雄质但不相同的成员之间的同源重组（HR）基因家族和b）促进整个基因组和中的序列变异的产生转向耐药性的发展。使用基因组编辑技术，诱变和SMRT 测序技术，我们试图发现TLS聚合酶在人类疟疾中的作用寄生虫，恶性疟原虫。我们提出的研究将发现疟原虫DNA修复的独特方面，这对于了解疟疾以及一般研究基因组维持的人。我们的目标是设计的为了直接影响疟疾的重要临床方面，寄生虫的发展承诺耐药性并逃避宿主免疫系统。这项研究涉及一个重要而被忽视的寄生虫生物学方面。