Trypanosome transmembrane kinases

锥虫跨膜激酶

基本信息

批准号：
8445189
负责人：
Marilyn Parsons
金额：
$ 28.35万
依托单位：
SEATTLE BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-15 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445189
关键词：
African Trypanosomiasis Alleles Biological Biological Models Biology Blood Circulation Cell Communication Cell Death Cell division Cell physiology Cells Cellular biology Cessation of life Complex Coupled Coupling Defect Development Disease Dissection Drug Targeting Drug resistance Endocytosis Environment Enzymes Event Flagella Future Genes Genetic Growth Human Immune In Vitro Individual Infection Integral Membrane Protein Knock-out Leishmania Location Malignant Neoplasms Membrane Mitosis Molecular Monitor Nature Nutrient Outcome Parasites Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Phosphotransferases Play Population Protein Kinase Proteins RNA Interference Regulation Regulator Genes Research Resistance Risk Role Route Site Solutions Staging Stress Structure Suppressor Mutations System Testing Therapeutic Time Transmembrane Domain Trypanosoma Trypanosoma brucei brucei Trypanosoma cruzi Trypanosomiasis Vaccines Work analog biological adaptation to stress cell motility chemical genetics combat cost effective design extracellular genome sequencing human disease improved in vivo inhibitor/antagonist insight interest kinetosome knockout gene loss of function mouse model mutant novel novel therapeutics pathogen public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): The protozoan parasite Trypanosoma brucei subspecies are the causative agent of African sleeping sickness, a disease that is invariably fatal without treatment. T. brucei has served as a model system for the study of the related trypanosomatid pathogens Trypanosoma cruzi and Leishmania spp., and the three together infect over 12 million people worldwide. The absence of vaccines and the toxic nature of drugs that combat sleeping sickness make research into new drug targets imperative. With the release of the genome sequences of these three trypanosomatids, there are now important decisions as to which of many candidate targets to pursue. Protein kinases are a large class of enzymes that serve as drug targets in cancer and other diseases. They sense the extracellular or intracellular environment and regulate numerous cellular responses, including cell division, responses to stress, development, and death. This project proposes the use of conditional knockout and chemical genetic approaches to examine the roles of protein kinases likely to play a role in host-parasite interactions. We have prioritized two novel protein kinases that reside in T. brucei membranes at the flagellum and flagellar pocket. This region of the parasite plays a prominent role in cell motility and division, nutrient acquisition, and immune evasion mechanisms. Surprisingly, unlike other eukaryotic protein kinases, these kinases possess multiple membrane spanning domains, implying novel modes of information coupling. Our RNAi studies indicate that they are important in the pathogenic bloodstream stage and their location within the parasite predicts a significant role in host-parasite interactions. Conditional knockous of the kinases will firmly establish the role of the kinases in vitro and in a mouse model. A chemical genetic approach using mutant forms of the kinases will be pursued to determine whether specific drug inhibition causes the same phenotypes as absence of the protein, conclusively assessing the suitability of these protein kinases as drug targets and providing the opportunity to dissect the pathways in which the kinases function.

描述（由申请人提供）：原生动物寄生虫Brucei亚种是非洲睡病的病因，这种疾病总是致命而没有治疗的疾病。布雷西（T. brucei）一直是研究相关锥虫病原体Cruzi和Leishmania spp。研究的模型系统，三者一起感染了全球超过1200万人。疫苗的缺乏和对抗睡眠疾病的药物的毒性使得对新药物的研究必须进行研究。随着这三种锥虫的基因组序列的释放，现在有重要的决定要追求哪些候选目标。蛋白激酶是一大类酶，它们是癌症和其他疾病中的药物靶标。他们感觉到细胞外或细胞内环境，并调节许多细胞反应，包括细胞分裂，对压力，发育和死亡的反应。该项目提出使用条件敲除和化学遗传方法来检查可能在宿主 - 寄生虫相互作用中发挥作用的蛋白激酶的作用。我们优先考虑了存在于鞭毛和鞭毛口袋的T. Brucei膜。寄生虫的这个区域在细胞运动和分裂，养分获取和免疫逃避机制中起着重要作用。令人惊讶的是，与其他真核蛋白激酶不同，这些激酶具有多个膜跨度域，这意味着新型信息偶联模式。我们的RNAi研究表明，它们在致病性血液阶段很重要，它们在寄生虫中的位置预测了在宿主 - 寄生虫相互作用中的重要作用。激酶的条件性敲除将牢固确定激酶在体外和小鼠模型中的作用。将采用使用激酶突变形式的化学遗传方法，以确定特定的药物抑制是否引起与缺乏蛋白质相同的表型，最终评估这些蛋白激酶作为药物靶标的适用性，并提供解剖途径的机会，以使动力酶起作用。