Unravelling the molecular mechanisms regulating cell division in the malaria parasite

疟疾是仅次于艾滋病毒和结核病的由单一传染因子引起的第三大全球健康问题，影响数百万人，每年导致100万人死亡（http：//www.who.int/topics/malaria/）。抗疟药物出现抗药性和缺乏有效疫苗突出表明，迫切需要开发新的手段来控制这一疾病。这种疾病的症状是当疟原虫侵入人体红细胞并每两天繁殖多次时引起的，最终导致红细胞的破坏，随后进一步入侵和细胞分裂。这些寄生虫细胞中的一些可能停止分裂，它们成为性细胞（雄性和雌性配子体）。当雌蚊叮咬受感染的人时，它们会沿着血液摄入寄生虫，这就触发了蚊子肠道内的寄生虫性细胞。雄配子母细胞进行快速细胞分裂，产生八个雄配子，然后使雌配子受精，寄生虫的生命周期在蚊子肠道中继续。在进一步的发育和繁殖之后，寄生虫移动到蚊子的唾液腺，并再次传给新的人类宿主。寄生虫在血细胞中和在性发育期间的分裂是非常不同的，但这两者对寄生虫都是必不可少的。如果寄生虫不能在血液中繁殖和分裂，那么它就不会引起疾病，如果雄配子母细胞不能分裂，那么寄生虫传输将被阻止。因此，了解寄生虫如何在这两个阶段繁殖和分裂是至关重要的，这样我们就可以通过开发适当的药物来开发干扰它们的方法。控制寄生虫中这两种类型细胞分裂的分子知之甚少。这里提出的项目是确定它们是什么以及它们如何工作。我们可以从使用模型系统中收集的知识开始，并将其应用于寄生虫。例如，在酵母和其他充分研究的系统中，一种称为后期促进复合物/细胞周期体（APC/C）的蛋白质复合物在细胞增殖和分裂中起关键作用。它被其他蛋白质激活，例如一种称为细胞分裂周期蛋白20（CDC 20）的蛋白质。这些蛋白质还可以通过添加或去除小的“标签”来进一步调节，例如可以打开或关闭特定功能的磷酸基团。我们最近在疟原虫中鉴定了其中一种蛋白质（CDC 20），并表明它在调节雄配子形成中起关键作用，而且它本身也受到磷酸标签的调节。在初步工作表明，我们的方法是可行的，我们已经获得的证据APC/C蛋白复合物的成分存在于寄生虫内繁殖的红细胞和男性性细胞。最近在分析疟疾基因方面的进展使我们能够研究这些分子的功能。例如，我们可以看到如果蛋白质不再产生会发生什么，如果用荧光标记物实验性地标记它们，我们可以在显微镜下看到它们在寄生虫中的位置。因此，我们现在可以进一步探索了解疟疾中的细胞分裂是如何由这些不同的分子控制的。我们还将研究这些分子是如何相互作用的，这项研究将使我们能够确定寄生虫生长和繁殖的关键机制，这可能是开发新的抗疟疾治疗方法的目标。我们的研究可以确定在红细胞中寄生虫细胞分裂和雄性配子形成中重要的分子靶标，因此可以有效对抗人类疾病的阶段或通过蚊子从一个个体传播到另一个个体。

Malaria is the third largest global health problem caused by a single infectious agent after HIV and TB, affecting millions of people, and resulting in one million deaths annually (http://www.who.int/topics/malaria/). The emergence of resistance to antimalarial drugs and the lack of any effective vaccine highlight the great need to develop new tools to control the disease. The symptoms of the disease are caused when the malaria parasite invades human red blood cells and multiplies many times every two days eventually leading to destruction of red blood cells and followed by further invasion and cell division. Some of these parasite cells may cease to divide and they become sex cells (male and female gametocytes). When a female mosquito bites an infected person they ingest parasites along with the blood and this acts as a trigger to activate the parasite sex cells within the mosquito gut. The male gametocytes undergo rapid cell division to produce eight male gametes, which then fertilise the female gametes and the parasite life cycle continues in the mosquito gut. After further development and multiplication the parasite moves to the mosquito's salivary glands and is passed again to a new human host.The divisions made by parasites in blood cells and during sexual development are very different, but both are essential for the parasite If the parasite was unable to multiply and divide in the blood stream then it would not cause disease and if the male gametocytes were unable to divide then parasite transmissionwould be blocked. Therefore it is critically important to understand how the parasite multiplies and divides at these two stages so that we can develop ways to interfere with them by developing appropriate drugs. The molecules that control these two types of cell division in the parasite are very poorly understood. The project proposed here is to identify what they are and how they work. We can start by using the knowledge gathered in model systems and applying this in the parasite. For example in yeast and other well-studied systems, a complex of proteins called the anaphase promoting complex/cyclosome (APC/C), plays a key role in cell multiplication and division. It is activated by the action of other proteins for example one called the cell division cycle protein-20 (CDC20). These proteins are also further regulated by the addition or removal of small 'tags', for example phosphate groups that can turn on or turn off particular functions.We have recently identified one of these proteins (CDC20) in the malaria parasite and shown that it has a key role in regulating male gamete formation, and also that it is itself regulated by addition of phosphate tags. In preliminary work showing that our approach is feasible, we have obtained evidence for the presence of components of the APC/C protein complex in both the parasite multiplying within the red blood cell and in the male sex cell. Recent advances in analysing genes in malaria allow us to study the function of these molecules. For example, we can see what happens if the proteins are no longer made, and if they are tagged experimentally with a fluorescent marker we can see where they are located in the parasite under the microscope. Therefore, we are now in a position where we can explore further to understand how cell division in malaria is controlled by these different molecules. We will also study how these molecules interact together.This research will enable us to identify mechanisms essential for parasite growth and multiplication that might be targeted in the development of new anti-malarial treatments. Our study may identify molecular targets important in parasite cell division in red blood cells and in the formation of male gametes, and therefore effective against either the stage responsible for the disease in humans or the transmission from one individual to another through the mosquito.