CONTROL OF LEISHMANIA BY PROGRAMMED CELL DEATH (APOPTOSIS)

利什曼原虫引起人类疾病，临床症状从自愈性皮肤损伤到致命的内脏感染。此外，在流行地区，感染艾滋病毒的人特别容易感染利什曼原虫。对这种寄生虫的细胞生物学和致病机制缺乏了解，使得控制这种严重的全球健康风险的任务变得困难。在离家更近的地方，美国军事人员、他们的家人和访问或居住在流行地区的其他旅行者尤其关注这一问题。为了寻找新的方法来控制这种病原体，我们已经开始研究了解利什曼原虫的程序性细胞死亡（凋亡）的机制。我们已经证明，热休克或治疗的抗利什曼原虫药物之一，喷他丁，利什曼原虫细胞死亡诱导的哺乳动物细胞中看到的经典凋亡具有一些相似之处。我们正在寻找更明确的证据，存在一个凋亡程序在这些寄生虫克隆利什曼原虫同源的已知凋亡基因保守从线虫到人类。接下来，我们计划操纵利什曼原虫中的凋亡基因，以改变利什曼原虫中的细胞死亡途径，从而可以通过目前可用的药物轻松消除，并且具有与这些治疗相关的毒副作用较小。

The Leishmania parasite causes human disease with clinical symptoms ranging from-self healing cutaneous lesions to a fatal visceral infection. Additionally, in endemic areas, people infected with HIV are especially prone to Leishmania infection. The lack of understanding of cell biology and pathogenic mechanisms of this parasite makes the task of controlling this grave, worldwide health risk difficult. Closer to home it is particularly of concern to U.S. military personnel, their families and other travellers visiting or living in the endemic areas. To find novel methods for control of this pathogen,we have initiated study to understand the mechanism of programmed cell death (apoptosis) in Leishmania. We have demonstrated that Leishmania cell death induced by heat shock or treatment with one of the anti-leishmanial drugs,pentastam, bears some similarities to classical apoptosis seen in mammalian cells. We are seeking more definitive evidence of the existence of an apoptotic program in these parasites by cloning Leishmanial homolgues of known apototic genes conserved from nematodes to humans. Next,we plan to manipulate apoptotic genes in Leishmania so as to alter the cell death pathway in Leishmania parasite thus can be eliminated with ease by the currently availabe drugs and has less toxic side effects commonly asociated with these therapies.