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Harnessing the Unique Biogenesis of the Apicomplexan plastid organelle forAntimalarial Targets

利用顶复体质体细胞器的独特生物发生来实现抗疟靶点

基本信息

批准号：
10170226
负责人：
Ellen Yeh
金额：
$ 58.63万
依托单位：
STANFORD UNIVERSITY
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：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10170226
关键词：
5 year old Animal Model Antimalarials Apicomplexa Babesiosis Back Benchmarking Biochemical Biogenesis Biological Assay Biology Blood Candidate Disease Gene Cell physiology Cells Cessation of life Chemicals Child Clindamycin Clinical Co-Immunoprecipitations Complement Complex Defect Disease Drug Targeting Enzymes Escherichia coli Eukaryota Foundations Gene Expression Genes Genetic Screening Genome Goals Growth Indoles Laboratories Life Malaria Molecular Morbidity - disease rate Mutation Organelles Orthologous Gene Parasite resistance Parasites Parasitic Diseases Pathogenesis Pathway interactions Phenotype Plasmodium Plasmodium falciparum Plastids Pregnant Women Process Protein Import Proteins Publishing Reaction Reporter Resistance Role Sequence Analysis Tertiary Protein Structure Testing Therapeutic Intervention Toxic effect Toxoplasmosis Tryptophan Validation alpha-glycerophosphoric acid base design disorder control drug discovery gene product genome sequencing global health human pathogen innovation insight isopentenyl pyrophosphate knock-down member mortality mutant new therapeutic target novel pathogen prevent resistance mechanism success whole genome

项目摘要

Abstract/ Project summary Malaria caused by Plasmodium spp parasites is a leading cause of morbidity and mortality globally. The emergence of resistance to frontline antimalarial drugs threatens to wipe out progress made in disease control and set back efforts toward eradication. New drug targets are urgently needed to circumvent current resistance mechanisms. The unique biology of Plasmodium spp and related human pathogens, compared to their mammalian hosts, can be leveraged to discover pathogen-specific drug targets that minimize host toxicity. A prime example of the pathogen's distinct biology is the non-photosynthetic plastid organelle, or apicoplast. Critical proteins that govern the biogenesis – growth, division, and inheritance – of the apicoplast during parasite replication remain mysterious, though compounds that block apicoplast biogenesis, such as clindamycin, are used clinically to prevent malaria and treat malaria, babesiosis, and toxoplasmosis. Because apicoplast biogenesis is required in every proliferative stage and conserved among parasites, it presents untapped opportunities to discover pathogen-specific drug targets effective across life stages and against multiple pathogens. Our long-term goal is to discover the molecular mechanisms of apicoplast biogenesis and exploit the machinery involved as antimalarial targets. The objective of this project is to identify and functionally characterize genes required for apicoplast biogenesis in blood-stage P. falciparum, since many essential, but as yet unidentified, genes are required for this complex process. My laboratory has laid the foundation to achieve this objective by successfully designing innovative approaches to discover new molecular players. This proposal will identify previously unknown genes required for apicoplast biogenesis using a new forward genetic screen and begin characterizing the biochemical and cellular functions of newly-validated genes. By identifying and functionally characterizing apicoplast biogenesis proteins, we will understand how this process can be disrupted to block pathogenesis in multiple stages of multiple eukaryotic pathogens.

摘要/项目摘要由疟原虫属寄生虫引起的疟疾是全球发病和死亡的主要原因。这对一线抗疟药物耐药性的出现可能会毁掉疾病控制方面取得的进展并阻碍根除努力。迫切需要新的药物靶点来规避当前的耐药性机制。与疟原虫属和相关人类病原体相比，其独特的生物学特性哺乳动物宿主可用于发现病原体特异性药物靶点，从而最大限度地减少宿主毒性。一个病原体独特生物学的主要例子是非光合作用质体细胞器或顶端质体。控制顶端质体生物发生（生长、分裂和遗传）的关键蛋白质尽管阻断顶质体生物发生的化合物，例如克林霉素，临床用于预防疟疾和治疗疟疾、巴贝西虫病和弓形体病。因为每个增殖阶段都需要顶端质体生物发生，并且在寄生虫中保守，它提出发现跨生命阶段有效的病原体特异性药物靶标的尚未开发的机会多种病原体。我们的长期目标是发现顶端质体生物发生的分子机制和利用所涉及的机器作为抗疟目标。该项目的目标是确定并在功能上描述血液阶段恶性疟原虫顶质体生物发生所需的基因，因为许多基因是必需的，但目前尚未确定这一复杂过程需要基因。我的实验室奠定了基础通过成功设计创新方法来发现新的分子参与者来实现这一目标。该提案将使用新的前向方法来识别顶端质体生物发生所需的先前未知的基因遗传筛选并开始表征新验证基因的生化和细胞功能。经过识别和功能表征顶端质体生物发生蛋白，我们将了解这个过程是如何进行的可以被破坏以阻断多种真核病原体的多个阶段的发病机制。