Telomere structure and function in Trypanosoma brucei

描述：(申请人提供)：这项建议的目的是 布氏锥虫端粒结构与功能的研究 布氏锥虫作为模式系统的潜力，有助于理解 哺乳动物细胞的端粒结构、合成和调节。具体的 目的是(1)鉴定和鉴定与端粒相互作用的蛋白质 在布氏锥虫中重复和(2)鉴定布氏锥虫的端粒酶复合体。 布鲁塞。非洲锥虫病有两个主要表现：人类疾病 被称为睡眠病和动物疾病Nagana(意思是失去 祖鲁语中的精灵)。锥虫病是赤道非洲的地方病， 在那里，它通过格洛西纳，也就是采采人在人和动物之间传播。这个 非洲本土动物几乎普遍受到感染，提供了大量的 潜在的人类病原体的蓄水池。人类局部流行是一种严重的 现实和日益增长的威胁。如果不治疗，锥虫病会迅速蔓延 致命的，每年可能导致大约10万人死亡。可用的 治疗方法并不令人满意，而且往往无效。其中一个主要原因是 因为非洲锥虫的持久性是他们独特而高效的 逃避哺乳动物免疫反应的机制。在一个称为 抗原变异，大多数锥虫种群被破坏 对一种变异的表面糖蛋白(VSG)外壳的免疫反应，但 单个锥虫使用数百个VSG的曲目来切换它们的VSG 基因，逃避破坏，并播种一连串的寄生虫血症。成为 在表达时，VSG基因必须位于端粒‘表达位点’。 尽管抗原变异引起了人们对锥虫端粒的关注， 几乎没有研究专门针对了解 锥体端粒结构及维护。哺乳动物的端粒有 引起了人们的极大关注，因为它们在细胞衰老和 癌症。随着大多数体细胞哺乳动物细胞的复制，它们的端粒变短， 对细胞可以分裂的次数进行限制。克服这一切 通过重新激活端粒酶进行限制是许多步骤中必要的一步。 导致癌症的基因变化。正因为如此，靶向药物 人们正在寻找端粒酶来治疗癌症。这类药物还可能 对治疗锥虫病有重要价值。有重要的 锥虫的端粒与人类的相似之处，所以锥虫 将是一个研究与人类有关的事件的有用模型 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.