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

• 批准号: 7729688
• 负责人: ROBERTO DOCAMPO
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 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/7729688
• 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

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）：布氏锥虫是昏睡病或非洲锥虫病的病原体。据世界卫生组织称，撒哈拉以南非洲有6 000多万人面临感染风险，每年发病300- 500 000例，造成55 000人死亡。自1970年以来，非洲锥虫病再次出现，化疗仍然不能令人满意，特别是对晚期病例。酸钙体是一种致密的酸性细胞器，具有高浓度的磷，以焦磷酸盐和多磷酸盐与钙和其他阳离子络合的形式存在。酸钙体膜含有许多泵（Ca 2 +-ATP酶、V-H+-ATP酶、H+-PPase）、交换剂（Na+/H+、Ca 2 +/H+）和通道（水通道蛋白），而其基质含有与焦磷酸盐和多磷酸盐代谢相关的酶。在几种病原微生物以及绿色衣藻和黏菌盘基网柄藻中发现了酸钙体。细菌中酸钙体的鉴定和人类血小板致密颗粒与酸钙体相似的发现表明，这种细胞器要么出现在细菌和真核生物谱系分化之前，要么独立地通过趋同进化而出现。酸钙体的一些潜在功能是阳离子和磷的储存，以及其参与焦磷酸盐和多磷酸盐代谢、钙稳态、维持细胞内pH稳态和钙离子调节。T.布氏杆菌是研究酸钙体的极好模型，我们的目标是了解其组成和功能。近年来，我们已经证明了这种细胞器中存在哺乳动物细胞中不存在的新型酶，这导致了化合物（焦磷酸盐类似物）的发现，这些化合物在由几种寄生虫引起的疾病的动物模型中产生根治作用。对T.布氏杆菌可能导致化学治疗剂的新靶点的鉴定。本论文将重点研究T.布氏杆菌，跨膜蛋白对该细胞器的靶向机制，以及焦磷酸盐和多磷酸盐代谢在布氏杆菌中的作用。布氏生长和发育。公共卫生关系：我们的目标是找到干扰布氏锥虫代谢途径的方法，作为控制由这种寄生虫和类似寄生虫引起的感染的策略。多磷酸盐和酸钙体代谢途径可能是新的杀锥虫剂的良好靶点，本工作旨在测试多磷酸盐和酸钙体的功能和意义。布鲁塞。