Role of Clp proteins in the biogenesis of the malaria parasite plastid

Clp 蛋白在疟原虫质体生物发生中的作用

• 批准号: 9226266
• 负责人: Vasant Muralidharan
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-07 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9226266
• 关键词: ATP phosphohydrolase; Adverse effects; Affect; Algae; Antibiotics; Antimalarials; Area; Automobile Driving; Bacteria; Biochemical; Biogenesis; Biological; Biological Assay; Biological Process; Biology; CRISPR/Cas technology; Carrier Proteins; Cell division; Cells; Cessation of life; Chloroplasts; Chromosome Mapping; Clinical; Cloning; Complex; Data; Disease; Drug Targeting; Drug resistance; Erythrocytes; Eukaryotic Cell; Gene Targeting; Genes; Genetic; Genetic Materials; Genome engineering; Goals; Growth; Hand; Human; In Vitro; Malaria; Measures; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Chaperones; Nuclear; Organelles; Parasites; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Plants; Plasmodium; Plasmodium falciparum; Plastids; Play; Process; Protein Family; Protein Import; Proteins; Protocols documentation; Research; Resistance; Resistance development; Role; Series; Signal Transduction; System; Testing; Usher Proteins; Vaccines; Virulence Factors; Work; base; complex R; conditional mutant; daughter cell; drug development; endosymbiont; experimental study; genetic manipulation; genetic regulatory protein; human disease; improved; in vivo; insight; killings; knock-down; mortality; novel; obligate intracellular parasite; pathogen; protein transport; proteostasis; resistant strain; segregation; small molecule; success

Plasmodium falciparum is a deadly parasite that causes malaria in humans and is responsible for nearly 600,000 deaths very year. Malaria is endemic in large regions of the world infecting nearly ~300 million people every year. There are no effective vaccines against malaria and antimalarial drugs are the mainstay of treatment. Unfortunately, the parasite has gained resistance to all clinically available antimalarial drugs and these drug-resistant strains are spreading throughout the world. This is threatening all the progress that has been made against this disease in the last decade. Thus, it is imperative that we constantly identify potential drug targets to stay ahead of this nefarious disease. The parasites from the genus Plasmodium that cause malaria are single celled, eukaryotic pathogens. Since human cells are also eukaryotic, it can be tricky to develop drugs that specifically kill the parasite and don't have too many side effects. The parasitic Plasmodium cell is amazingly complex with two organelles that carry their own genetic material, the mitochondrion and a unique plastid of algal origin known as the apicoplast. The apicoplast is present only in the parasite and not in the human host. This makes it an ideal drug target since attacking the apicoplast will affect only the parasite and not the human host. In fact, some antibiotics have shown success as antimalarial drugs because they target essential biological processes in the apicoplast. However, the molecular mechanisms that drive the biology of this unique parasite organelle remain unknown, which hampers antimalarial drug development. The proposed studies target an important set of genes that we hypothesize to act as key regulators for the biogenesis of the apicoplast. Our preliminary data show that one of the targeted genes is essential for parasite growth underscoring the importance of this pathway in the biology of P. falciparum. We will apply genetic, cellular, and biochemical approaches to characterize the various roles that these genes play in the biogenesis of this essential parasite organelle. Attaining the aims of this proposal will uncover the novel biology of the apicoplast and identify parasite-specific essential proteins that can be targeted for antimalarial drug development.

恶性疟原虫是一种致命的寄生虫，会导致人类疟疾，几乎负责 一年60万人死亡。疟疾在世界的大型地区是地方性的，感染了近3亿人 每年。没有针对疟疾的有效疫苗，抗疟药是 治疗。不幸的是，该寄生虫对所有临床上可用的抗疟药都具有抵抗力 这些抗药性菌株正在世界各地传播。这威胁着所有取得的进步 在过去的十年中是针对这种疾病的。因此，我们必须不断地确定潜力 药物靶标保持领先于这种邪恶疾病。引起疟原虫属的寄生虫 疟疾是单细胞的真核病原体。由于人类细胞也是真核的，因此很难 开发专门杀死寄生虫的药物，没有太多副作用。寄生疟原虫 细胞非常复杂，有两个带有自己遗传物质的细胞器，线粒体和一个细胞器 藻类起源的独特质体被称为apicoplast。 apicoplast仅存在于寄生虫中，而不存在于 人类主持人。这使其成为理想的药物目标，因为攻击apicoplast只会影响寄生虫 而不是人类主持人。实际上，某些抗生素已作为抗疟药表现出成功，因为它们 靶标的靶标生物学过程。但是，驱动驱动的分子机制 这种独特的寄生虫细胞器的生物学仍然未知，这阻碍了抗疟药的发育。这 提出的研究针对一组重要的基因，我们假设这些基因是作为关键调节剂 蛋白质成形体的生物发生。我们的初步数据表明，靶向基因之一对于寄生虫至关重要 增长强调了这种途径在恶性疟原虫生物学中的重要性。我们将应用遗传， 细胞和生化方法来表征这些基因在生物发生中起的各种作用 这个必需的寄生虫细胞器。达到该提议的目的将揭示 蛋白酶成形棒和识别寄生虫特异性的必需蛋白质，可以针对抗疟药 发展。