MECHANISM OF ANTIGENIC VARIATION IN TRYPANOSOMA BRUCEI

锥虫和相关原虫寄生虫引起一系列 人及其牲畜的疾病(例如查加斯病和睡眠 疾病)。血栖寄生虫布氏锥虫逃脱 通过定期的抗原变异来破坏免疫 改变一种变异型细胞表面糖蛋白的生产 (VSG)涂到下一层。我们将研究免疫的遗传基础-- 逃避。重点将放在VSG基因的转录控制上 以及对表达部位、染色体重要性的理解 和核结构对VSG基因的激活。我们还将研究 表达位点相关基因的生物学作用，即 与VSG基因协同转录。 我们对血管紧张素转换酶基因的转录特别感兴趣 一种对药物α-不敏感的新型RNA聚合酶 阿马尼丁。我们将对这种RNA聚合酶进行表征并比较 它与其他真核RNA的转录特异性 聚合酶。我们将测试药物的干扰能力 与VSG基因的转录切换有关。我们将调查 蛋白质编码基因转录的重要性 锥虫体及相关组织中的氨基鸟苷不敏感RNA聚合酶 动粒体虫。这些研究的目的是为了了解 RNA编码蛋白转录的生物学作用 聚合酶II和另一种尚未鉴定的RNA聚合酶。一个 药物治疗的理论基础可能会产生。 为了方便对这些原生动物寄生虫的分子分析 将进一步开发布鲁氏毛滴虫的DNA转化系统。我们 将构建可用于导入外源基因的载体 变成锥虫。这些载体将被设计成类似于VSG 染色体重排和基因表达位点 VSG基因的转录调控将被研究。

Trypanosomes and related protozoan parasites cause a range of diseases man and his livestock (e.g. Chagas disease and sleeping sickness). The blood-dwelling parasite Trypanosoma brucei escapes immune-destruction through antigenic variation, by periodically changing the production of one variant cell surface glycoprotein (VSG) coat to the next. We will study the genetic basis of immune- evasion. The focus will be on transcriptional control of VSG genes and on understanding the importance of expression site, chromosome and nuclear structure for VSG gene activation. We will also study the biological role of expression site associated genes, that are coordinately transcribed with the VSG gene. We are particularly interested in transcription of VSG genes by a novel type of RNA polymerase that is insensitive to the drug alpha- amanitin. We will characterize this RNA polymerase and compare its transcriptional specificity to that of other eukaryotic RNA polymerases. We will test drugs for their capability to interfere with transcription switching of VSG genes. We will survey the importance of transcription of protein-coding genes by alpha- amanitin insensitive RNA polymerases in trypanosomes and related kinetoplastida. These studies are aimed at understanding the biological role of transcription of protein coding get by RNA polymerase II and another as yet unidentified RNA polymerase. A rationale for drug therapy may result. To facilitate the molecular analysis of these protozoan parasites will further develop a DNA transfection system for T.brucei. We will construct vectors that can be used to introduce foreign genes into trypanosomes. The vectors will be engineered to resemble VSG gene expression sites with which chromosomal rearrangements and transcript control of VSG genes will be studied.