Investigating host kinase modulation of erythrocyte deformability during Plasmodium falciparum invasion

研究恶性疟原虫入侵期间红细胞变形能力的宿主激酶调节

基本信息

批准号：
10431764
负责人：
Patrice Valerie Groomes
金额：
$ 3.2万
依托单位：
HARVARD SCHOOL OF PUBLIC HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10431764
关键词：
Actins Actomyosin Affect Anemia Ankyrins Antimalarials Apical Biology Blood CSNK2A1 gene Cells Cellular biology Communication Communities Complex Culicidae Cytolysis Cytoskeleton Data Data Analyses Data Set Development Disease Drug Targeting Drug resistance Erythrocytes FDA approved Fellowship Fibrosis Genetic Glean Hematologic Neoplasms Hematological Disease Hematology Hemolysis Hereditary Spherocytosis Human Individual Industry Integration Host Factors Knock-out Leukocytes Life Cycle Stages Ligands Malaria Mechanics Mediating Membrane Mentorship Merozoite Surface Protein 1 Morphology Motor Nonmuscle Myosin Type IIA Osmotic Fragility test Parasites Parasitology Pathology Penetration Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Plasmodium Plasmodium falciparum Process Proteins Proteomics Public Health Schools Research Role SYK gene Scientist Series Signal Transduction Signal Transduction Pathway Spectrin Stimulus Streptococcus Structure Surface Technical Expertise Thrombocytopenia Validation adducin beta Spectrin casein kinase II cell type chemical genetics cost drug repurposing flexibility genetic analysis inhibitor/antagonist insight kinase inhibitor mutant new therapeutic target novel parasite invasion phosphoproteomics receptor skill acquisition small molecule inhibitor tool

项目摘要

PROJECT SUMMARY/ABSTRACT Malaria is a devastating disease caused by obligate intracellular Plasmodium parasites that infect millions of people every year: In 2017 alone, 219 million people were infected by the parasite and 435,000 people were killed. Every antimalarial deployed to date has been counteracted by cases of drug resistance, highlighting a desperate need for novel drug targets.Targeting host factors is an underexplored alternative approach to increasing barriers to drug resistance in malaria. This strategy has the potential to uncover targets required for multiple Plasmodium species due to overlaps in host requirements. Additionally, many Plasmodium host factors are already FDA approved drug targets, making a compelling case for drug repurposing. The red blood cell (RBC) is not a passive bystander during Plasmodium invasion; mounting evidence suggests the RBC host is co-opted into modifying its own deformability during parasite attachment & invasion to reduce the energy costs of parasite entry. These changes are driven by phosphorylation of the RBC cytoskeleton. Host RBC kinases TRPM7, Casein Kinase II (CKII), and Syk are FDA approved drug targets postulated to phosphorylate the RBC cytoskeleton during P. falciparum invasion. I hypothesize that Plasmodium signaling to the RBC cytoskeleton during merozoite invasion occurs through these kinases to modulate RBC deformability and facilitate parasite entry. My preliminary data indicates that P. falciparum invasion efficiency is compromised in individual RBC knockouts targeting TRPM7, CSNK2A1, and SYK kinases. Using an integrated genetic, chemical genetic, and phosphoproteomics approach, this proposal seeks to investigate TRPM7, CKII, and Syk kinase contributions to RBC deformation during P. falciparum invasion, validate small molecule inhibitors targeting these kinases, and elucidate parasite stimuli and downstream effectors mediating host kinase signal transduction during P. falciparum invasion. If successful, these studies will uncover more about the basic biology of Plasmodium invasion, identify promising host targets for drug repurposing in blood stage malaria, and facilitate the development of broad spectrum antimalarial compounds with increased barriers to drug resistance. Finally, as many additional hematological disorders are affected by these kinases—including macrothrombocytopenia & arterial fibrosis (TRPM7), hereditary spherocytosis & Streptococcus-mediates hemolysis (Syk), and several hematological malignancies (CKII)—insights gleaned from these functional analyses will benefit both parasitology and hematology communities. The proposed research will be carried out as part of my doctoral dissertation studies at the Harvard T.H. Chan School of Public Health. During this fellowship I will acquire & strengthen technical skills including chemical genetics, parasitology, and proteomics; and fine-tune data analysis, scientific communication, mentorship, and professional development skills needed to become an independent research scientist in industry.

项目摘要/摘要疟疾是由专性细胞内质质寄生虫引起的毁灭性疾病，该疾病感染了数百万每年的人：仅在2017年，就有2.19亿人被寄生虫感染，43.5万人被感染被杀。迄今为止部署的每种抗疟药都被耐药性案件所抵消，强调了迫切需要新的药物目标。靶向宿主因素是一种毫无疑问的替代方法增加疟疾耐药性的障碍。该策略有可能发现目标由于宿主需求重叠而引起的多个疟原虫物种。此外，许多疟原虫宿主因子已经是FDA批准的药物靶标，这是一个令人信服的药物重新使用案例。红细胞（RBC）在疟原虫入侵期间不是被动的旁观者。越野证据建议RBC主机选择在寄生虫附着和入侵期间修改其自身的可变形性降低寄生虫进入的能源成本。这些变化是由RBC细胞骨架的磷酸化驱动的。宿主RBC激酶TRPM7，酪蛋白激酶II（CKII）和SYK是FDA批准的药物靶标恶性疟原虫入侵期间，磷酸化RBC细胞骨架。我假设疟原虫信号传导 Merozoite入侵期间的RBC细胞骨架通过这些激酶进行调节RBC可变形性并促进寄生虫进入。我的初步数据表明恶性疟原虫的入侵效率受到损害在单独的RBC敲除中，靶向TRPM7，CSNK2A1和SYK激酶。使用综合遗传，化学遗传和磷蛋白质组学方法，该提案试图研究TRPM7，CKII和SYK激酶对恶性疟原虫入侵期间RBC变形的贡献，验证针对这些激酶的小分子抑制剂，并阐明寄生虫刺激和下游在恶性疟原虫入侵期间介导宿主激酶信号转移的效果。如果成功，这些研究将发现更多有关疟原虫侵袭的基本生物学，确定有希望的宿主靶标的药物在血液阶段疟疾中重新利用，并支持广谱抗疟疾化合物的发展具有耐药性障碍的增加。最后，由于许多其他血液学疾病受到这些激酶 - 包括巨栓细胞减少症和动脉纤维化（TRPM7），遗传性球细胞增多症和链球菌 - 溶血（SYK）和几个血液学恶性肿瘤（CKII） - 直觉收集通过这些功能分析将使寄生虫学和血液学群落受益。拟议的研究将作为我在哈佛T.H.博士学位论文研究的一部分进行。陈公共卫生学院。在此奖学金期间，我将获得并增强技术技能，包括化学技能遗传学，寄生虫学和蛋白质组学；以及微调数据分析，科学沟通，精神验证和专业发展技能需要成为工业领域的独立研究科学家。