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：
10631907
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
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/10631907
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：疟疾仍然是生活在热带和热带地区的人们发病和死亡的主要原因。世界亚热带地区寄生虫持续产生序列多样性的能力。他们的基因组中的一个主要因素是无法形成有效的红细胞阶段然而，我们在疫苗和耐药性问题方面仍然存在重大差距。了解寄生虫基因组的维持方式我们的长期目标是确定途径。这对于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可变性和基因组可塑性。跨损伤 (TLS) 聚合酶是一种特殊的 DNA 聚合酶，能够持续 DNA 通过损坏基础和困难的模板进行合成，尽管它们以容易出错的方式实现这一点在模型系统中，TLS 聚合酶仅产生大多数新突变。灵长类疟疾基因组中存在两种 TLS 聚合酶，Rev 1 和 pol ζ。这些聚合酶在寄生虫基因组的维持中发挥着至关重要的作用，并有助于维持和疟疾的发病机制 a) 通过促进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) 有助于整个基因组和体内序列变异的产生转向使用基因组编辑技术、诱变和 SMRT 来发展耐药性。测序技术，我们试图揭示 TLS 聚合酶在人类疟疾中的作用寄生虫，恶性疟原虫。我们提出的研究将揭示疟原虫 DNA 修复的独特方面，这对于了解疟疾以及研究一般基因组维护的人是我们的目标。对疟疾的重要临床方面、寄生虫的发展倾向产生直接影响这项研究解决了一个重要且被忽视的问题。寄生虫生物学的各个方面。