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，导致人类疟疾， 每年有60万人死亡。疟疾是世界上大部分地区的地方病，感染了近3亿人 每年没有有效的疟疾疫苗，抗疟药物是治疗疟疾的主要手段。 治疗不幸的是，这种寄生虫已经对所有临床上可用的抗疟药物产生了抗药性， 这些耐药菌株正在全世界蔓延。这威胁到了所有的进步， 在过去的十年里，针对这种疾病。因此，我们必须不断确定潜在的 药物靶点，以保持领先于这种邪恶的疾病。疟原虫属的寄生虫会导致 疟疾是单细胞真核病原体。由于人类细胞也是真核生物， 开发出专门杀死寄生虫的药物，而不会有太多的副作用。寄生的疟原虫 细胞是惊人的复杂，有两个细胞器，携带自己的遗传物质， 藻类起源的独特质体，称为顶质体。顶质体只存在于寄生虫体内， 人类宿主。这使得它成为一个理想的药物靶点，因为攻击顶质体将只影响寄生虫 而不是人类宿主。事实上，一些抗生素作为抗疟疾药物已经取得了成功，因为它们 靶向顶质体中的基本生物过程。然而，驱动细胞凋亡的分子机制 这种独特的寄生虫细胞器的生物学仍然未知，这阻碍了抗疟疾药物的开发。的 拟议的研究针对一组重要的基因，我们假设这些基因是基因表达的关键调控因子。 顶质体的生物发生。我们的初步数据表明，其中一个靶基因是寄生虫所必需的， 生长强调了这一途径在恶性疟原虫生物学中的重要性。我们将应用基因， 细胞和生物化学方法来表征这些基因在生物发生中发挥的各种作用 这个重要的寄生虫细胞器。实现这一提议的目标将揭示新的生物学的 顶质体并鉴定可作为抗疟药物靶向的寄生虫特异性必需蛋白 发展