FATTY ACID BIOSYTHESIS IN CRYPTOSPORIDIUM PARVUM

小隐孢子虫中的脂肪酸生物合成

• 批准号: 6336055
• 负责人: GUAN ZHU
• 金额: $ 19.65万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336055
• 关键词: Cryptosporidium; enzyme activity; fatty acid biosynthesis; fatty acid synthase; gene expression; laboratory rabbit; microorganism metabolism; protein localization

DESCRIPTION: (Adapted from Applicant's Abstract) Cryptosporidium parvum causes one of the opportunistic infections (OI) in AIDS patients for which no treatment is yet known. Although many drugs have been tested against the OI, knowledge about the presence of target enzymes, biosynthetic pathways, and expression or regulation are virtually unknown. The applicant's preliminary data indicate that several fatty acid synthase (FAS) genes are present in C. parvum (CpFAS) and that their size, organization and functional domains differ from those of humans. These genes appear to be functional, since their transcripts were detected in sporozoites and intracellular stages and the growth of C. parvum in vitro was inhibited by a FAS inhibitor. The discovery of CpFAS genes suggests that this apicomplexan might synthesize fatty acids de novo, thus providing clues for drug development against cyptosporidiosis. Because most parasitic protozoa are auxotrophs for fatty acids, this discovery also opens a new vista for protozoan biochemistry. The investigator's long term goal is to study the potential of apicomplexan fatty acid biosynthesis as a useful target for drug development. The specific aims of this proposal are: 1.Characterize the CpFAS gene structure, transcription level and subcellular localization during the life cycle of the parasite. 2. Elucidate the function of CpFAS by the analysis of substrate preference, intermediate and final fatty acid products using recombinant CpFAS proteins expressed in bacteria or yeast 3.Determine whether fatty acid biosynthesis can serve as a rational target for drug development by screening FAS analogues against C. parvum in vitro and in vivo. Completion of these specific aims will either support or refute the investigator's hypothesis that fatty acid biosynthesis in C. parvum is sufficiently different from its host to be exploited for drug design target against cryptosporidiosis. The outcome expected is to overcome a major obstacle for therapy against this OI of AIDS patients.

描述：（改编自申请人的摘要）cryptosporidium parvum原因 艾滋病患者中的机会感染之一（OI） 治疗尚不知道。尽管许多药物已经针对OI进行了测试，但是 了解靶酶，生物合成途径和 表达或调节实际上是未知的。申请人的初步 数据表明C. Parvum（CPFA），它们的大小，组织和功能域不同 来自人类的人。这些基因似乎是功能性的，因为它们的 在孢子岩和细胞内阶段检测到转录本，并在 FAS抑制剂抑制了体外C. parvum的生长。发现 CPFAS基因表明，该Apicomplexan可能合成脂肪酸DE Novo，从而为针对Cyptosporidiosis的药物开发提供了线索。 因为大多数寄生虫原生动物是用于脂肪酸的人营养物，所以这种发现 还为原生动物生物化学打开了新的远景。调查员的长期 目的是研究Apicomplexan脂肪酸生物合成的潜力 药物开发的有用目标。该提案的具体目的是： 1.特征CPFA基因结构，转录水平和亚细胞 寄生虫生命周期期间的定位。 2。阐明该功能 通过分析底物偏好，中间和最终脂肪的分析CPFA 使用在细菌或酵母中表达的重组CPFA蛋白的酸产物 3.确定脂肪酸生物合成是否可以作为合理目标 通过在体外和IN筛选针对Parvum C. parvum C. parvum的FAS类似物来开发药物 体内。这些特定目标的完成将支持或反驳 研究者假设脂肪酸的生物合成孢子虫是 与宿主的足够不同，可以利用用于药物设计目标 反对隐孢子虫病。预期的结果是克服一个主要障碍 用于针对这种艾滋病患者的治疗。