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艾滋病毒/艾滋病、结核病或疟疾等更广为人知的疾病。这些被忽视的疾病影响着世界各地数以百万计的人，导致数千人死亡，并影响更多人饲养牲畜、农作物或谋生的能力。没有疫苗可以预防它们，药物治疗有严重的副作用或不是完全有效。对这些寄生虫的代谢途径的研究可能对它们的生存至关重要，但可能在宿主中找不到对应的代谢途径，这可能为开发新的治疗方法提供潜在的新靶点的信息。这项应用的目的是继续我们对酸性钙体和聚磷酸盐在布氏锥虫中作用的研究。我们的假设是，锥虫体内酸性钙体和聚磷酸功能的特征将导致对这些寄生虫生物学的重要洞察，并最终 抗寄生虫干预的新靶点。我们在锥虫体内发现了一条新的代谢途径，涉及肌醇焦磷酸酯的合成，并发现了一些多聚磷酸结合蛋白。这些发现，加上最近发现的聚磷酸在炎症反应中的作用和作为原始伴侣的作用，极大地增加了我们发现新的新陈代谢途径和抗寄生虫药物靶点的机会。我们将研究肌醇焦磷酸盐(InsPPs)、聚磷酸盐(PolyP)合成和酸性钙体之间的联系，InsPPs的功能，以及聚磷酸盐在锥虫体内作为伴侣的作用。

 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.