GENETICS OF DRUG RESISTANCE AND PATHOGENIC MECHANISMS IN P FALCIPARUM MALARIA

恶性疟的耐药遗传学及致病机制

• 批准号: 6098943
• 负责人: Thomas E Wellems
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6098943
• 关键词: Africa; Plasmodium falciparum; antimalarial agents; chloroquine; clinical research; dihydrofolate reductase; drug resistance; enzyme linked immunosorbent assay; epidemiology; gene expression; host organism interaction; human subject; intracellular parasitism; malaria; microorganism genetics; nucleic acid sequence; pharmacogenetics; protozoal antigen

Of the four Plasmodium species generally responsible for human malaria, Plasmodium falciparum produces the most severe disease and causes almost all deaths. P. falciparum also has become resistant to chloroquine, once the first-line drug for the prophylaxis and treatment of malaria. The Malaria Genetics Section of the Laboratory of Parasitic Diseases conducts basic research on factors that govern the drug response, pathogenesis and transmission of P. falciparum malaria. For more than a decade, a principal theme in this work has been the search for the gene responsible for chloroquine resistance. This search has required development of previously nonexistent genetic resources and technology, including P. falciparum pedigrees for linkage analysis, detailed microsatellite linkage maps of the genome and gene transformation methods for erythrocyte-stage parasites. Current research in the Section includes the following projects: 1) the mechanisms of chloroquine resistance and quinine resistance in P. falciparum malaria; 2) targets of other leading antimalarial drugs, including such dihydrofolate-reductase (DHFR) inhibitors such as pyrimethamine, WR99210, proguanil and cycloguanil; 3) the expression and variation of the var genes which modulate the adhesive and antigenic character of parasitized red blood cells; 4) hemoglobinopathies and severity of malaria in African children; 5) a genetic defect of chromosome 12 that adversely affects the development of male gametocytes; 6) function of ebl-1, a candidate gene for an invasion phenotype linked to P.falciparum chromosome 13.

一般而言，四种疟原虫种类中 恶性疟原虫产生人类疟疾 最严重的疾病，几乎导致所有死亡。恶性疟原虫 也对曾经的一线药物氯喹产生了耐药性 用于预防和治疗疟疾。疟疾遗传学 寄生虫病实验室科开展基础研究 药物反应、发病机制和控制因素的研究 恶性疟原虫疟疾的传播。十多年来， 这项工作的主题是寻找基因 负责氯喹耐药性。此搜索需要 开发以前不存在的遗传资源和 技术，包括用于连锁分析的恶性疟原虫谱系， 基因组和基因的详细微卫星连锁图 红细胞期寄生虫的转化方法。当前的 该部分的研究包括以下项目：1） P. 氯喹和奎宁耐药机制 恶性疟疾； 2) 其他主要抗疟药物的靶点， 包括二氢叶酸还原酶 (DHFR) 抑制剂，例如 乙胺嘧啶、WR99210、氯胍和环胍； 3） 调节 var 基因的表达和变异 寄生红细胞的粘附和抗原特性； 4） 非洲儿童的血红蛋白病和疟疾的严重程度； 5）一个 12号染色体的遗传缺陷对身体产生不利影响 雄性配子细胞的发育； 6) ebl-1的函数，候选者 与恶性疟原虫染色体相关的入侵表型基因 13.