Telomere structure and function in Trypanosoma brucei

描述：（由申请人提供）：本提案的目的是 研究布氏锥虫端粒的结构和功能， 潜力T。作为一个模型系统，有助于了解 哺乳动物细胞中端粒结构、合成和调节。具体 目的是（1）鉴定和表征与端粒相互作用的蛋白质， T.布氏锥虫端粒酶复合体的特征。 布鲁塞。非洲锥虫病有两种主要表现： 被称为睡眠病和动物疾病Nagana（意思是失去 祖鲁语（Zulu）。锥虫病是赤道非洲的地方病， 在人类和动物之间通过舌蝇传播。的 非洲本土动物群几乎普遍受到感染， 潜在人类病原体的储存库。人类疫源性流行病是一种严重的 现实和日益严重的威胁。如果不治疗，锥虫病迅速 致命的，每年可能导致大约10万人死亡。可用 治疗不能令人满意，而且常常无效。的主要原因之一 非洲锥虫的持续存在是它们独特而有效的 逃避哺乳动物免疫反应的机制。在一个被称为 抗原变异，大多数锥虫种群被破坏， 对变异表面糖蛋白（VSG）涂层的免疫反应，但 个体锥虫使用数百个VSG的全部功能来转换它们的VSG， 基因，逃避破坏，并种子连续波的寄生虫血症。是 当VSG基因表达时，VSG基因必须位于端粒的“表达位点”。 尽管抗原变异引起了人们对锥虫端粒的注意， 几乎没有专门针对理解 锥虫端粒的结构和维持。哺乳动物的端粒 由于它们在细胞衰老中的核心作用， 癌当大多数哺乳动物体细胞复制时，它们的端粒缩短， 限制了细胞分裂的次数。克服这一 通过重新激活端粒酶，限制是许多步骤中的一个必要步骤， 导致癌症的基因变化正因为如此， 正在寻找端粒酶用于治疗癌症。这些药物也可以 对治疗锥虫病有价值。存在显著 锥虫和人类端粒的相似性， 将是一个有用的模型，在其中研究的事件，是有关人类 衰老和癌症

DESCRIPTION: (provided by the applicant): The objective of this proposal is to study telomere structure and function in Trypanosoma brucei and to explore the potential of T. brucei as a model system, to contribute to the understanding of telomere structure, synthesis and regulation in mammalian cells. The specific aims are (1) to identify and characterize proteins that interact with telomeric repeats in T. brucei and (2) to characterize the telomerase complex of T. brucei. African trypanosomiasis has two major manifestations: the human disease known as Sleeping Sickness and the animal disease Nagana (meaning loss of spirits in the Zulu language). Trypanosomiasis is endemic in equatorial Africa, where it is transmitted, among humans and animals, by Glossina, the Tsetse. The native African fauna are almost universally infected, providing a vast reservoir of potential human pathogens. Focal human epidemics are a serious reality and an increasing threat. If untreated, trypanosomiasis is rapidly fatal, and probably kills around 100,000 people annually. The available treatments are unsatisfactory and often ineffective. One of the major reasons for the persistence of African trypanosomes is their unique and efficient mechanism to evade the mammalian immune response. In a process known as Antigenic Variation, the majority of the trypanosome population is destroyed by the immune responses to a variant surface glycoprotein (VSG) coat, but individual trypanosomes switch their VSG, using a repertoire of hundreds of VSG genes, evade destruction, and seed successive waves of parasitemia. To be expressed, a VSG gene has to be located at a telomeric 'expression site'. Although antigenic variation has drawn attention to trypanosome telomeres, there has been almost no research targeted specifically to understanding trypanosome telomere structure and maintenance. Mammalian telomeres have attracted much attention, because of their central role in cell senescence and cancer. As most somatic mammalian cells replicate, their telomeres shorten, placing a limit on the number of times a cell can divide. Overcoming this restriction, by reactivating telomerase, is a necessary step among the many genetic changes that lead to cancer. Because of this, drugs that target telomerase are being sought for the treatment of cancer. Such drugs could also be valuable in the treatment of trypanosomiasis. There are significant similarities between the telomeres of trypanosomes and humans, so trypanosomes would be a useful model in which to study events that are relevant to human aging and cancer.