PROTEIN DEGRADATION IN P FALCIPARUM

恶性疟原虫中的蛋白质降解

• 批准号: 3131134
• 负责人: DAVID L VANDER JAGT
• 金额: $ 10.39万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3131134
• 关键词: Plasmodium falciparum; aminoacid; antibody formation; antimalarial agents; drug design /synthesis /production; enzyme linked immunosorbent assay; enzyme structure; growth /development; hemoglobin; high performance liquid chromatography; host organism interaction; human tissue; immunochemistry; lysosomes; monoclonal antibody; peptidases; proteolysis

The goal of this research project is to elucidate the functions of parasite proteases in the growth and maturation of the malarial parasite Plasmodium falciparum. The goal is related to a long- range objective of developing new antimalarial drugs targeted at parasite proteases, especially proteases involved in parasite-host interactions. The specific aims of this project are 1) to characterize acid and neutral proteases and to determine their roles in the degradation of hemoglobin; 2) to determine there roles of ATP-dependent and ATP-independent non-lysosomal proteolysis in the development of P.falciparum; 3) to elucidate the site of action of chloroquine; 4) to determine the roles of proteases in merozoite-host interactions. The following hypotheses will be tested: 1. Digestion of host cytosol by malarial parasites involves acid proteases in the parasite's food vacuole but also involves non- lysosomal pathways for the degradation of hemoglobin. 2. Chloroquine interferes with the digestion of hemoglobin by diverting hemin from sequestration into malarial pigment. The actual inhibitor of parasite growth is free hemin which inhibits proteolysis. 3. Chloroquine resistance results from mutations which increase the efficiency of sequestration of hemin into malarial pigment. 4. Surface proteases of merozoite-stage parasites are active participants in the process of invasion of erythrocytes by P.falciparum. Parasite proteases will be purified by HPLC procedures and will be characterized Cytochemical and immunocytochemical studies of cellular proteases will be carried out. Proteases will be carried out. Proteases will be isolated from various morphological states of the intraerythrocytic parasite.

这项研究项目的目的是阐明 寄生虫蛋白酶在疟疾生长成熟中的作用 寄生虫恶性疟原虫。这个目标与一个长期的- 针对以下目标开发抗疟疾新药的范围目标 寄生虫蛋白酶，尤其是与寄生虫宿主有关的蛋白酶 互动。 该项目的具体目标是1)表征酸和 中性蛋白水解酶及其在降解中的作用 2)确定三磷酸腺苷(ATP)依赖和 三磷酸腺苷非依赖性非溶酶体蛋白水解酶在血管内皮细胞发育中的作用 恶性疟原虫；3)阐明氯喹的作用部位；4) 确定蛋白水解酶在裂殖子宿主中的作用 互动。 我们将检验以下假设： 1.疟疾寄生虫对宿主胞浆的消化涉及酸 寄生虫食物液泡中的蛋白酶，但也涉及非 血红蛋白降解的溶酶体途径。 2.氯喹通过以下方式干扰血红蛋白的消化 将氯化血红素从封存中转移到疟疾色素中。这个 实际抑制寄生虫生长的是游离氯化高铁血红素，它抑制 蛋白质分解。 3.氯喹抗药性是由增加的突变引起的 将氯化高铁血红素固定在疟疾色素中的效率。 4.裂殖子期寄生虫表面蛋白水解酶活性 红细胞侵袭过程中的参与者 恶性疟原虫。 寄生虫蛋白水解酶将通过高效液相程序进行纯化，并将 BE细胞化学和免疫细胞化学研究 将进行细胞蛋白酶的研究。蛋白水解酶将被携带 出去。蛋白水解酶将从各种形态中分离出来 红血球内寄生虫。