GENETICS OF DRUG RESISTANCE AND PATHOGENIC MECHANISMS IN P FALCIPARUM MALARIA

在四种疟原虫中，一般 恶性疟原虫导致人类疟疾 最严重的疾病，并导致几乎所有的死亡。恶性疟原虫 也对氯喹产生了抗药性，氯喹曾是一线药物 用于预防和治疗疟疾。疟疾遗传学 寄生虫病实验室科室开展基础工作 药物反应、发病机制及影响因素的研究进展 恶性疟疾的传播。十多年来，一个 这部作品的主要主题是寻找基因 对氯喹抗药性负责。这项搜索需要 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家系， 基因组和基因的详细微卫星连锁图谱 红细胞期寄生虫的转化方法。当前 该科的研究包括以下项目：1) 铜绿假单胞菌对氯喹和奎宁的抗性机制 恶性疟疾；2)其他主要抗疟疾药物的靶标， 包括二氢叶酸还原酶(DHFR)抑制剂，如 乙胺嘧啶、WR99210、普罗瓜尼和环瓜尼；3) 调节血管紧张素转换酶的var基因的表达和变异 寄生红细胞的粘附性和抗原性 非洲儿童中的血红蛋白疾病和疟疾的严重程度；5)a 12号染色体的遗传缺陷，对 雄配子体的发育；6)候选基因EBL-1的功能 与恶性疟原虫染色体连锁的侵袭表型基因 13.

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.