The role of polyphosphate and acidocalcisomes in Trypanosoma brucei

多磷酸盐和酸钙体在布氏锥虫中的作用

基本信息

批准号：
7879425
负责人：
ROBERTO DOCAMPO
金额：
$ 36.75万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7879425
关键词：
AIDS/HIV problem Abbreviations Adverse effects Affect Africa South of the Sahara African Trypanosomiasis Aging Animal Disease Models Animal Model Anthrax disease Antifibrinolytic Agents Antifungal Agents Apoptosis Azoles Bacteria Benznidazole Biology Blood Platelets Ca(2+)-Transporting ATPase Calcium Cations Cattle Cells Cessation of life Chagas Disease Chemistry Chlamydomonas reinhardtii Coagulants Complex Cytoplasmic Granules Development Dictyostelium discoideum Diphosphates Disease Dysentery Energy-Filtering Transmission Electron Microscopy Enzymes Evolution Fossils Gene Expression Genetic Gentian Violet Goals Grant Green Algae Growth and Development function Hemorrhage Homeostasis Human Incidence Infection Infection Control Integral Membrane Protein Knowledge Laboratories Lead Leishmaniasis Life Maintenance Malaria Malignant Neoplasms Mammalian Cell Membrane Metabolic Metabolic Pathway Metabolism Modeling Molecular Molecular Genetics Morbidity - disease rate Names Nature Nifurtimox Organelles Osmoregulation Osteoporosis Parasite Control Parasites Persons Pharmaceutical Preparations Phenotype Phosphorus Physarum polycephalum Physiology Platelet Activation Play Polymers Polyphosphate kinase Polyphosphates Proteins Proteomics Proton-Translocating ATPases Protons Pump Risk Role Set protein Signal Transduction Sterile coverings Testing Text Trypanocidal Agents Trypanosoma Trypanosoma brucei brucei Trypanosoma cruzi Trypanosomiasis Tuberculosis Vaccines Virulence Work World Health Organization analog bisphosphonate calcium metabolism career chemotherapeutic agent chemotherapy comparative design inhibitor/antagonist man microorganism mortality novel pH Homeostasis prevent proton-translocating pyrophosphatase public health relevance pyrophosphatase tool trafficking water channel wound

项目摘要

DESCRIPTION (provided by applicant): Trypanosoma brucei is the causative agent of sleeping sickness or African trypanosomiasis. According to the World Health Organization, over 60 million persons in sub-Saharan Africa are at risk of infection with an incidence of 300-500,000 cases per year resulting in 55,000 deaths. African trypanosomiasis has been reemerging since 1970, and chemotherapy remains unsatisfactory, especially for advanced cases. The acidocalcisome is a dense, acidic organelle with a high concentration of phosphorus present as pyrophosphate and polyphosphate complexed with calcium, and other cations. The acidocalcisome membrane contains a number of pumps (Ca2+- ATPase, V-H+-ATPase, H+-PPase), exchangers (Na+/H+, Ca2+/H+), and channels (aquaporins), while its matrix contains enzymes related to pyrophosphate and polyphosphate metabolism. Acidocalcisomes have been found in several pathogenic microorganisms as well as in the green alga Chlamydomonas reinhardtii, and the slime mold Dictyostelium discoideum. The identification of the acidocalcisome in bacteria and the finding that human platelet dense granules are similar to acidocalcisomes, indicate that this organelle either appeared before the divergence of bacterial and eukaryotic lineages or independently by convergent evolution. Some of the potential functions of the acidocalcisome are the storage of cations and phosphorus, and its participation in pyrophosphate and polyphosphate metabolism, calcium homeostasis, maintenance of intracellular pH homeostasis, and osmoregulation. T. brucei is an excellent model to study the acidocalcisome and our goal is to know its composition and function. In recent years we have demonstrated the presence of novel enzymes in this organelle that are absent from mammalian cells and this led to the finding of compounds (pyrophosphate analogs) that produced radical cures in animal models of diseases caused by several parasites. Further exploration of the composition and function of the acidocalcisome in T. brucei could lead to the identification of new targets for chemotherapeutic agents. We will focus on studying the composition and function of the acidocalcisome proteins of T. brucei, the targeting mechanism of transmembrane proteins to this organelle, and the roles of pyrophosphate and polyphosphate metabolism in T. brucei growth and development. PUBLIC HEALTH RELEVANCE: Our goal is to find ways of interfering with Trypanosoma brucei metabolic pathways as a strategy of controlling infections caused by this and similar parasites. The polyphosphate and acidocalcisome metabolic pathways may be good targets for new trypanocidal agents and this work is designed to test the function and significance of polyphosphate and acidocalcisomes of T. brucei.

描述（由申请人提供）：Brucei锥虫是睡眠疾病或非洲锥虫病的病因。根据世界卫生组织的数据，撒哈拉以南非洲的6000万人处于感染的危险中，每年发生300-500,000例，导致55,000例死亡。自1970年以来，非洲锥虫病一直在重新出现，化疗仍然不令人满意，尤其是对于晚期病例。酸钙化体是一种致密的酸性细胞器，具有高浓度的磷含量为焦磷酸盐和多磷酸，与钙和其他阳离子构成。酸性膜膜包含许多泵（Ca2+ATPase，V-H+-ATPase，H+-ppase），交换器（Na+/H+，Ca2+/H+）和通道（Aquaporins），而其基质含有与吡啶并磷酸磷酸盐和多磷酸磷酸盐和多磷酸化代磷酸盐相关的。在几种致病的微生物以及绿色的藻类衣原体Reinhardtii和粘液模具dictyostelium discoideum中都发现了酸环异构体。细菌中酸钙化体的鉴定以及人血小板致密颗粒类似于酸钙化体的发现，表明该细胞器要么出现在细菌和真核谱系发散之前，要么通过收敛进化而独立于。酸钙化体的某些潜在功能是阳离子和磷的储存，及其参与焦磷酸盐和多磷酸代谢，钙稳态，维持细胞内pH稳态和渗透压。布鲁氏链球菌是研究酸钙化体的绝佳模型，我们的目标是了解其组成和功能。近年来，我们已经证明了该细胞器中没有新型酶的存在，这些酶在哺乳动物细胞中不存在，这导致发现在由几种寄生虫引起的疾病动物模型中产生了根本治疗的化合物（焦磷酸类似物）。进一步探索t. brucei中酸钙化体的组成和功能可能导致鉴定化学治疗剂的新靶标。我们将重点研究t. brucei的酸钙化蛋白的组成和功能，跨膜蛋白的靶向机理对该细胞器的靶向机制，以及焦磷酸盐和多磷酸代谢在t. brucei生长和发育中的作用。公共卫生相关性：我们的目标是找到干扰布鲁氏锥虫代谢途径的方法，以此作为控制由这种和类似寄生虫引起的感染的策略。多磷酸盐和酸钙化代谢途径可能是新型锥虫剂的良好靶标，这项工作旨在测试Brucei T. brucei的多磷酸盐和酸钙化体的功能和重要性。