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，可引起人类疟疾，并导致近乎 每年有 60 万人死亡。疟疾在世界大部分地区流行，感染近 3 亿人 每年。目前还没有针对疟疾的有效疫苗，抗疟药物是主要手段 治疗。不幸的是，这种寄生虫已经对所有临床可用的抗疟药物产生了耐药性，并且 这些耐药菌株正在全世界蔓延。这正在威胁到已经取得的所有进展 在过去的十年中针对这种疾病进行了研究。因此，我们必须不断识别潜在的 药物的目标是领先于这种邪恶的疾病。疟原虫属的寄生虫会引起 疟疾是单细胞真核病原体。由于人类细胞也是真核细胞，因此很难 开发专门杀死寄生虫且没有太多副作用的药物。寄生疟原虫 细胞非常复杂，有两种细胞器，它们携带自己的遗传物质，线粒体和 藻类起源的独特质体，称为顶端质体。顶质体仅存在于寄生虫中，而不存在于 人类宿主。这使其成为理想的药物靶点，因为攻击顶质体只会影响寄生虫 而不是人类宿主。事实上，一些抗生素作为抗疟药已取得成功，因为它们 针对顶端质体中的重要生物过程。然而，驱动该现象的分子机制 这种独特的寄生虫细胞器的生物学特性仍然未知，这阻碍了抗疟药物的开发。这 拟议的研究针对一组重要的基因，我们假设它们是 顶端质体的生物发生。我们的初步数据表明，目标基因之一对于寄生虫至关重要 生长强调了该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发挥的各种作用 这种重要的寄生虫细胞器。实现该提案的目标将揭示该生物的新颖生物学特性 顶端质体并鉴定可作为抗疟药物靶点的寄生虫特异性必需蛋白 发展。