Calcium signaling in Trypanosoma brucei

布氏锥虫中的钙信号传导

• 批准号: 8722815
• 负责人: ROBERTO DOCAMPO
• 金额: $ 37.27万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-04 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722815
• 关键词: AIDS/HIV problem; ATP Synthesis Pathway; Acquired Immunodeficiency Syndrome; Address; Adverse effects; Affect; African Trypanosomiasis; Antiparasitic Agents; Apoptotic; Attention; Biology; Calcium; Calcium Signaling; Calcium ion; Cattle; Cell Death; Cell physiology; Cells; Cessation of life; Chagas Disease; Communicable Diseases; Coupling; Development; Disease; Drug usage; Endoplasmic Reticulum; Essential Genes; Eukaryotic Cell; Evolution; Future; Generations; Goals; Growth; Growth and Development function; Homeostasis; Human; ITPR1 gene; Infection; Infection Control; Inositol; Intervention; Laboratories; Lead; Leishmaniasis; Life; Link; Malaria; Mediating; Metabolic; Metabolic Pathway; Mitochondria; Mitochondrial Proteins; Molecular; Morbidity - disease rate; Nature; Organelles; Orthologous Gene; Orthophosphate; Parasites; Pathogenicity; Pathway interactions; Pattern; Permeability; Pharmaceutical Preparations; Polymers; Property; Proteins; Reactive Oxygen Species; Regulation; Role; Safety; Shapes; Signal Pathway; Signal Transduction; Therapeutic; Tropical Disease; Trypanocidal Agents; Trypanosoma; Trypanosoma brucei brucei; Tuberculosis; Vaccines; Work; calcium uniporter; cost; design; insight; mortality; neglect; novel; novel therapeutic intervention; prevent; public health relevance; receptor; spatiotemporal; therapeutic target; uptake

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.

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。对这些寄生虫的代谢途径的研究可能对其生存至关重要，但可能无法在其宿主中找到等效的代谢途径，这可以提供有关潜在新靶点的信息，可用于开发新的治疗方法。通道和转运蛋白是许多治疗上有用的药剂的靶标，并且它们作为治疗靶标仍然显著地未被开发，甚至作为抗寄生虫剂更是如此。 本申请的目的是研究布氏锥虫中的钙离子（Ca 2+）信号。我们的假设是，锥虫中涉及Ca 2+信号传导的途径的表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novl靶点的重要见解。我们最近发现，1，4，5-三磷酸肌醇受体（IP 3R）是一种钙释放通道，定位于T.布鲁塞。这是该通道的高度独特的定位，其通常存在于脊椎动物细胞的内质网（ER）中。IP 3R是大多数真核细胞中负责启动细胞内Ca 2+信号传导的主要胞质靶标。通过IP 3R介导的Ca 2+信号途径刺激对生命至关重要的活动，但在某些条件下IP 3R介导的Ca 2+信号被破坏，导致细胞死亡。例如，Ca 2+特异性地从IP 3Rs的流动可以引起线粒体通透性转换并激活凋亡级联，表明该途径具有潜在的治疗意义。这种钙释放通道的存在下，在acidocalcisomes，一个酸性的钙储存细胞器高度丰富的聚磷酸盐（聚合物的正磷酸盐），表明独特的调节机制和功能。通过IP 3R-线粒体钙单向转运体（MCU）的紧密连接促进来自IP 3R的Ca 2+的流动。几年前，我们的实验室在锥虫中发现了MCU的活性，并将此信息用于鉴定哺乳动物MCU的分子性质。我们最近在T.布氏杆菌，并发现它是必不可少的生长和建立感染。我们未来的目标是通过TbIP 3R来表征Ca 2+信号传导及其在生长中的作用，以及其对细胞代谢活性的调节作用。 线粒体通过TbMCU。