Calcium signaling 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。通道和转运体是许多治疗有用药物的靶点，它们作为治疗靶点仍然被严重低估，更不用说作为抗寄生虫剂了。本应用的目的是研究布氏锥虫体内的钙离子信号转导。我们的假设是，锥虫体内涉及钙信号通路的特征将导致对这些寄生虫的生物学、真核细胞的进化以及最终抗寄生虫干预的新靶点的重要洞察。我们最近发现，肌醇1，4，5-三磷酸受体(IP3R)是一种钙释放通道，定位于布氏毛滴虫的酸性钙体。这是该通道的一个非常独特的定位，该通道通常存在于脊椎动物细胞的内质网(ER)。在大多数真核细胞中，IP3R是启动细胞内钙信号的主要胞浆靶标。通过IP3R释放的钙离子刺激生命中至关重要的活动，但在某些情况下，IP3R介导的钙信号被颠覆，导致细胞死亡。例如，IP3Rs特异性的钙离子流可以引起线粒体通透性转变，激活细胞凋亡级联反应，提示这一途径具有潜在的治疗意义。酸性钙体是一种富含聚磷酸盐(正磷酸盐的聚合物)的酸性钙储存细胞器，这种钙释放通道的存在表明了独特的调节机制和功能。IP3R与线粒体钙单转运体(MCU)的紧密连接促进了钙离子从IP3Rs的流动。几年前，我们的实验室在锥虫体内发现了MCU的活性，并利用这一信息来鉴定哺乳动物MCU的分子性质。我们最近鉴定了布鲁氏毛滴虫的MCU同源基因，发现它对生长和感染的建立是必不可少的。我们未来的目标是表征通过TbIP3R的钙信号及其在生长中的作用，以及它对细胞代谢活动的调节作用。 线粒体通过TbMCU。

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. Channels and transporters are targets of many therapeutically useful agents and they remain significantly under-explored as therapeutic targets, even more so as antiparasitic agents. The goal of this application is to study calcium ion (Ca2+) signaling in Trypanosoma brucei. Our hypothesis is that the characterization of the pathways involving Ca2+ signaling in trypanosomes will lead to important insights into the biology of these parasites, the evolution of eukaryotic cells, and ultimately novl targets for anti-parasitic intervention. We recently discovered that the inositol 1,4,5-trisphosphate receptor (IP3R), a Ca2+ release channel, localizes to acidocalcisomes of T. brucei. This is a highly unique localization for this channel, which is usually present in the endoplasmic reticulum (ER) of vertebrate cells. The IP3R is the primary cytosolic target responsible for the initiation of intracellular Ca2+ signaling in most eukaryotic cells. The releas of Ca2+ via IP3Rs stimulates activities critical for life, but under some conditions IP3R-mediated Ca2+ signals are subverted to cause cell death. For example, flow of Ca2+ specifically from IP3Rs can cause mitochondrial permeability transition and activate the apoptotic cascade, suggesting this pathway as of potential therapeutic significance. The presence of this Ca2+ release channel in acidocalcisomes, an acidic calcium storage organelle highly rich in polyphosphate (a polymer of orthophosphate), suggests unique regulatory mechanisms and functions. Flow of Ca2+ from IP3Rs is facilitated by the close IP3R-mitochondrial calcium uniporter (MCU) connection. Several years ago, our laboratory discovered the activity of MCU in trypanosomes and this information was used to identify the molecular nature of the mammalian MCU. We recently characterized the MCU ortholog in T. brucei and found it to be essential for growth and establishment of infection. Our future goals are to characterize Ca2+ signaling through the TbIP3R and its role in growth, and its regulatory role on the metabolic activity of the mitochondria through the TbMCU.