Heat Shock Protein Prenylation in Malaria Parasites

疟原虫中的热激蛋白异戊二烯化

• 批准号: 9893706
• 负责人: Emily S Mathews
• 金额: $ 1.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2020-01-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893706
• 关键词: Abbreviations; Affect; Antimalarials; Artemisinins; Biological; Biological Process; Biology; Blood; C-terminal; Cell physiology; Cellular Stress; Cessation of life; Chemicals; Client; Clinical; Combined Modality Therapy; Communicable Diseases; Complement; Culicidae; Data; Development; Diphosphates; Ensure; Falciparum Malaria; Fever; Future; Goals; Growth; Growth and Development function; Heat shock proteins; Heat-Shock Response; Infection; Interruption; Knowledge; Label; Lead; Lipids; Malaria; Mediating; Mediator of activation protein; Membrane; Mentors; Mentorship; Molecular; Molecular Chaperones; Parasites; Partner in relationship; Pathway interactions; Plasmodium; Plasmodium falciparum; Plasmodium falciparum genome; Post-Translational Protein Processing; Protein Inhibition; Protein Isoprenylation; Proteins; Proteome; Proteomics; Regulation; Research; Research Proposals; Research Training; Resistance; Role; Signal Transduction; Stress; System; Testing; Training Activity; Transgenic Organisms; Work; asexual; base; career; drug development; experience; fitness; genetic manipulation; human mortality; innovation; knock-down; mutant; new therapeutic target; parasite genome; prenylation; prevent; protein farnesyltransferase; protein folding; protein function; skills; success; trafficking; transmission process

PROJECT SUMMARY/ABSTRACT Malaria is a significant contributor to global human mortality and accounts for an estimated 445,000 deaths and 216 million cases per year. The vast majority of malaria deaths result from Plasmodium falciparum infection. Resistance to available antimalarials continues to emerge including currently used artemisinin-based combination therapies. New therapeutic targets for treatment of malaria are greatly needed, and target-based drug development relies on our fundamental understanding of essential parasite biology. P. falciparum requires protein prenylation, the C-terminal post-translational lipid modification of proteins, for asexual replication. Our long term goal is to uncover the molecular basis of why prenylation is required by the malaria parasite for survival. We recently identified the complete prenylated proteome of blood-stage P. falciparum malaria parasites. Our preliminary studies revealed that PfHsp40 (PF3D7_1437900), a heat shock protein, is robustly prenylated. Heat shock proteins are necessary for protein folding and stabilization and their expression is upregulated under different cellular stresses including heat shock. P. falciparum experiences heat shock throughout its lifecycle and it is not surprising then that roughly 2% of the P. falciparum genome is dedicated to molecular chaperones such as heat shock proteins. The objective of this proposal is to establish the biological role and regulation of PfHsp40. The proposed studies will answer several fundamental questions including: What is the role of PfHsp40 in P. falciparum? Does prenylation influence the role of PfHsp40 in the parasite? Supported by strong preliminary data that indicate that this strategy will be successful, the objective will be met through two specific aims: 1) Determine the importance of PfHsp40 in asexual replication of P. falciparum; and 2) Determine the mechanism by which protein prenylation controls the biological role of PfHsp40. This approach is innovative, since it uses a combination of state-of-the-art genetic manipulation systems to directly establish the functional aspects of protein prenylation in Plasmodium. The proposed research is significant, because it will illuminate the role of PfHsp40 in the parasite, establish how prenylation influences the biological role of PfHsp40, and identify downstream proteins and pathways that require prenylation in the parasite. Furthermore, because heat shock proteins are found across taxa, the findings are likely to reveal broadly applicable concepts about heat shock protein function.

项目概要/摘要 疟疾是导致全球人类死亡的一个重要因素，估计造成 445,000 人死亡， 每年 2.16 亿例。绝大多数疟疾死亡是由恶性疟原虫感染引起的。 对现有抗疟药的耐药性不断出现，包括目前使用的青蒿素类药物 联合疗法。非常需要治疗疟疾的新治疗靶点，并且基于靶点 药物开发依赖于我们对基本寄生虫生物学的基本理解。恶性疟原虫需要 蛋白质异戊二烯化，蛋白质的 C 末端翻译后脂质修饰，用于无性复制。我们的 长期目标是揭示疟疾寄生虫为何需要异戊二烯化才能生存的分子基础。 我们最近鉴定了血液阶段恶性疟原虫疟疾寄生虫的完整异戊二烯化蛋白质组。我们的 初步研究表明，热休克蛋白 PfHsp40 (PF3D7_1437900) 被强异戊二烯化。热 休克蛋白对于蛋白质折叠和稳定是必需的，并且它们的表达在以下条件下上调： 不同的细胞应激，包括热休克。恶性疟原虫在其整个生命周期中都会经历热休克，并且 因此，大约 2% 的恶性疟原虫基因组专门用于分子伴侣，例如 如热休克蛋白。该提案的目的是确定 PfHsp40 的生物学作用和调节。 拟议的研究将回答几个基本问​​题，包括： PfHsp40 在 P. 恶性疟原虫？异戊二烯化是否会影响 PfHsp40 在寄生虫中的作用？有强有力的初步数据支持 表明该战略将会成功，该目标将通过两个具体目标来实现： 1) 确定 PfHsp40 在恶性疟原虫无性复制中的重要性； 2) 确定机制 蛋白质异戊二烯化控制 PfHsp40 的生物学作用。这种方法是创新的，因为它使用了 结合最先进的基因操作系统来直接建立蛋白质的功能方面 疟原虫中的异戊二烯化。拟议的研究意义重大，因为它将阐明 PfHsp40 的作用 在寄生虫中，确定异戊二烯化如何影响 PfHsp40 的生物学作用，并确定下游 寄生虫中需要异戊二烯化的蛋白质和途径。此外，由于热休克蛋白 在整个分类群中发现，这些发现可能揭示有关热休克蛋白功能的广泛适用的概念。