The roles of polyphosphate and acidocalcisomes in Trypanosoma brucei

 描述（由申请人提供）：与非洲锥虫病、恰加斯病和利什曼病相关的发病率和死亡率可能超过更知名的疾病，如艾滋病毒/艾滋病、结核病或疟疾。这些被忽视的疾病影响着全世界数百万人，造成数千人死亡，并影响到更多人养牛、种植作物或谋生的能力。没有疫苗可以预防它们，药物治疗有严重的副作用或不完全有效。这些寄生虫的代谢途径的研究，可能是必不可少的，他们的生存，但可能不会找到一个等价的对应在其主机可以提供信息的潜在的新目标，可以利用开发新的治疗方法。 本申请的目的是继续我们对布氏锥虫中酸钙体和多磷酸盐的作用的研究。我们的假设是，锥虫中酸钙体和多磷酸盐功能的表征将导致对这些寄生虫生物学的重要见解，并最终 抗寄生虫干预的新靶点。 我们已经确定了一种新的代谢途径，锥虫涉及肌醇焦磷酸的合成，并发现了一些聚磷酸结合蛋白。这些发现，加上最近发现的多磷酸盐在炎症反应中的作用和作为原始伴侣的作用，大大提高了我们发现新的代谢途径和抗寄生虫药物靶点的机会。我们将调查肌醇焦磷酸（InsPPs），聚磷酸（polyP）的合成，和acidocalcisomes之间的联系，InsPPs的功能，和多磷酸作为伴侣在锥虫的作用。

 DESCRIPTION (provided by applicant): The morbidity and mortality associated with African trypanosomiasis, Chagas disease, and leishmaniasis may exceed better-known conditions such as of HIV/AIDS, tuberculosis, or malaria. These neglected diseases affect millions of people around the world, causing thousands of deaths and affecting the ability of more people to raise cattle, and crops, or earn a living. No vaccines are available to prevent them and drug treatments have serious side effects or are not completely effective. The study of metabolic pathways in these parasites that may be essential for their survival but may not find an equivalent counterpart in their host could provide information on potential new targets that could be exploited for development of new therapeutic approaches. The goal of this application is to continue our studies of the roles of acidocalcisomes and polyphosphate in Trypanosoma brucei. Our hypothesis is that the characterization of the acidocalcisome and polyphosphate functions in trypanosomes will lead to important insights into the biology of these parasites, and ultimately novel targets for anti-parasitic intervention. We have identified a novel metabolic pathway in trypanosomes involving the synthesis of inositol pyrophosphates, and found a number of polyphosphate-binding proteins. These findings, together with the recent discoveries of the roles of polyphosphate in inflammatory reactions and as a primordial chaperone greatly enhance our chances to discover novel metabolic pathways and targets for anti- parasitic drugs. We will investigate the link between inositol pyrophosphates (InsPPs), polyphosphate (polyP) synthesis, and acidocalcisomes, the function of InsPPs, and the role of polyphosphate as a chaperone in trypanosomes.