Functional analysis of epigenetic regulators of malaria blood-stage proliferation and transmission

疟疾血期增殖和传播的表观遗传调节因子的功能分析

• 批准号: 10115577
• 负责人: Manoj T Duraisingh
• 金额: $ 39.88万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-20 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115577
• 关键词: Affect; Animal Model; Antigenic Variation; Antimalarials; Biochemical; Biochemical Genetics; Biological; Biology; Blood; Cell physiology; Cells; ChIP-seq; Chemicals; Clinical; Communicable Diseases; Critical Pathways; Culicidae; Data; Development; Disease; Drug Targeting; Drug resistance; Ensure; Environment; Enzymes; Epigenetic Process; Erythrocytes; Exhibits; Family; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Genetic study; Growth; Histone Deacetylase; Histones; Human; In Vitro; Infection; Lead; Life Cycle Stages; Link; Malaria; Mediator of activation protein; Morbidity - disease rate; Oocysts; Organ; Parasites; Pathogenesis; Phenotype; Plasmodium falciparum; Population; Process; Proteins; Regimen; Regulation; Research; Resources; Role; Scourge; Severity of illness; Sexual Development; Sirtuins; Specificity; Tertiary Protein Structure; Virulence; Work; asexual; chemical genetics; chronic infection; epigenetic regulation; epigenomics; genetic approach; inhibitor/antagonist; knock-down; mortality; mutant; new therapeutic target; novel therapeutics; paralogous gene; programs; protein expression; protein function; reverse genetics; small molecule inhibitor; success; therapeutic development; transcriptomics; transmission process; vector-borne

PROJECT SUMMARY Malaria remains a major global infectious disease, largely affecting people living in resource poor environments. Infection of humans with Plasmodium falciparum parasites results in significant morbidity and mortality. Drug- resistance is constantly undermining the usefulness of antimalarial regimens. It is imperative to identify new antimalarial drug targets to ensure the success of control and eradication efforts. Further, the call for malaria eradication requires an understanding of the determinants of parasite transmission. Plasmodium falciparum parasites utilize epigenetic machinery for the regulation of key processes within the parasitic life-cycle, including antigenic variation for persistence and pathogenesis during asexual proliferation, as well as for switching to sexual development for transmission through the parasitic life-cycle. We have obtained genetic evidence that the Class II histone deacetylases (HDACs) are essential for P. falciparum growth during the asexual cycle. We hypothesize that these P. falciparum HDACs regulate discrete and critical functions in the asexual and sexual biology of the parasite. Inhibition of these mechanisms will result in the specific killing of P. falciparum asexual and/or sexual forms. In this proposal, we will identify the essential functions of these enzymes that are responsible for asexual proliferation, conversion to the sexual stage, and sexual development for transmission. We will use a reverse genetics approach for the phenotypic analysis of mutant parasites in the asexual and sexual stages. We will probe the mechanistic basic of HDAC functions using a combination of bulk and single cell transcriptomics and epigenomics. Finally, we will uncover the precise mechanisms of action of the HDACs by dissecting the functions of their specific enzymatic domains, using biochemical and chemical genetic approaches. Together, these studies will serve to elucidate the functions of these critical epigenetic regulators in parasite biology relevant to asexual proliferation for virulence and sexual development for transmission, validating and characterizing these molecules as new targets for therapeutic development within the parasite.

项目总结 疟疾仍然是一种主要的全球传染病，在很大程度上影响着生活在资源匮乏环境中的人们。 人类感染恶性疟原虫会导致严重的发病率和死亡率。毒品-- 耐药性不断地破坏抗疟疾方案的有效性。当务之急是发现新的 抗疟疾药物目标，以确保控制和根除努力的成功。此外，对疟疾的呼吁 根除需要了解寄生虫传播的决定因素。 恶性疟原虫利用表观遗传机制调节体内的关键过程 寄生生命周期，包括在无性繁殖期间的持久性和致病机制的抗原变异， 以及转向性发育以通过寄生生命周期传播。我们已经获得了 第二类组蛋白脱乙酰酶(HDACs)是恶性疟原虫生长所必需的遗传证据 无性循环。我们假设这些恶性疟原虫HDAC调节离散的和关键的功能 寄生虫的无性和有性生物学。这些机制的抑制将导致对P. 恶性疟原虫无性和/或有性形式。 在这项提案中，我们将确定这些酶的基本功能，这些酶负责无性 繁殖，转变为性阶段，性发育以进行传播。我们将使用相反的方法 无性和有性阶段突变寄生虫表型分析的遗传学方法。我们会 结合块状和单细胞转录技术探讨HDAC功能的机制基础 表观基因组学。最后，我们将通过剖析HDAC的功能来揭示HDAC的精确作用机制 利用生化和化学遗传方法，对其特定的酶结构域进行分析。加在一起，这些 研究将有助于阐明这些关键的表观遗传调节因子在寄生虫生物学中的功能 用于毒力的无性繁殖和用于传播的性发展，验证和表征这些 分子作为寄生虫治疗发展的新靶点。