Calcium signaling in Trypanosoma brucei

布氏锥虫中的钙信号传导

基本信息

批准号：
8903755
负责人：
ROBERTO DOCAMPO
金额：
$ 37.5万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
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/8903755
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 Health 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 Trypanocidal Agents Trypanosoma Trypanosoma brucei brucei Tuberculosis Vaccines Work calcium uniporter cost design insight mortality neglect neglected tropical diseases novel novel therapeutic intervention prevent receptor spatiotemporal therapeutic target uptake

项目摘要

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众所周知的疾病，例如艾滋病毒/艾滋病、结核病或疟疾。这些被忽视的疾病影响着世界各地数百万人，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，但可能在宿主中找不到同等的对应物，可以提供有关潜在新靶标的信息，这些靶标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物的靶点，并且它们作为治疗靶点的探索仍然显着不足，作为抗寄生虫药物更是如此。此应用的目标是研究布氏锥虫中的钙离子 (Ca2+) 信号传导。我们的假设是，锥虫中涉及 Ca2+ 信号传导途径的表征将为了解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标提供重要见解。我们最近发现，肌醇 1,4,5-三磷酸受体 (IP3R)（一种 Ca2+ 释放通道）定位于 T. brucei 的酸钙体。这是该通道的高度独特的定位，通常存在于脊椎动物细胞的内质网（ER）中。 IP3R 是大多数真核细胞中负责启动细胞内 Ca2+ 信号传导的主要胞质靶标。通过 IP3R 释放 Ca2+ 会刺激对生命至关重要的活动，但在某些条件下，IP3R 介导的 Ca2+ 信号会被破坏，导致细胞死亡。例如，专门从 IP3R 流出的 Ca2+ 可以引起线粒体通透性转变并激活细胞凋亡级联，表明该途径具有潜在的治疗意义。酸性钙体（一种富含多磷酸盐（正磷酸盐的聚合物）的酸性钙储存细胞器）中存在这种 Ca2+ 释放通道，表明其具有独特的调节机制和功能。 IP3R-线粒体钙单向转运蛋白 (MCU) 的紧密连接促进了 Ca2+ 从 IP3R 的流动。几年前，我们的实验室发现了锥虫中 MCU 的活性，该信息被用来鉴定哺乳动物 MCU 的分子性质。我们最近对布氏锥虫的 MCU 直系同源物进行了表征，发现它对于生长和感染的建立至关重要。我们未来的目标是通过 TbIP3R 表征 Ca2+ 信号传导及其在生长中的作用及其对细胞代谢活动的调节作用线粒体通过 TbMCU。