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Characterization of Potassium Channels in the Human Parasite Trypanosoma Cruzi

人类寄生虫克氏锥虫钾通道的表征

基本信息

批准号：
8703605
负责人：
Veronica Jimenez
金额：
$ 24.42万
依托单位：
CALIFORNIA STATE UNIVERSITY FULLERTON
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：
2013-07-18 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8703605
关键词：
Ablation Benznidazole Blood Circulation Calcium-Activated Potassium Channel Cell Proliferation Regulation Cell membrane Cell physiology Cells Chagas Disease Complement Complex Congestive Heart Failure Disease Electrodes Environment Epidemiology FDA approved Feces Financial compensation Heart Diseases Homologous Gene Human Immigration Immunofluorescence Immunologic Insect Vectors Insecta Ion Channel Ions Kidney Knock-out Laboratories Latin America Life Life Cycle Stages Light Lipids Liposomes Maintenance Membrane Membrane Potentials Modification Molecular Molecular Profiling Nifurtimox Oocytes Osmolar Concentration Osmoregulation Parasites Pathology Pharmaceutical Preparations Physiological Play Potassium Channel Poverty Process Property Proteins Regulation Role Site Site-Directed Mutagenesis Staging Stress Trypanosoma cruzi Urine Work Xenopus laevis abstracting cellular imaging coping environmental change extracellular genetic manipulation gutted vector in vivo inward rectifier potassium channel mitochondrial membrane new therapeutic target overexpression patch clamp reconstitution response rural area success therapeutic target vector voltage clamp

项目摘要

Abstract Chagas disease is a zoonotic tropical pathology, caused by the protozoan parasite Trypanosoma cruzi. Endemic en Latin America, it is one of the leading causes of congestive heart failure in the world. Historically associated with poverty in rural areas, immigration and relocation of the vectors are changing the epidemiology of the disease, as evidenced by a substantial increase in the number of cases in the US. Treatment is restricted to nifurtimox and benznidazole, both of which are relatively toxic, have limited efficacy and are not approved by the FDA. Our laboratory has been working on the rational search for chemotherapeutic treatments for Chagas disease that can selectively target the parasite without compromising human cells. Ion channels are potential targets for selective drugs against a broad range of diseases because they are responsible for essential cellular functions like plasma membrane and mitochondrial membrane potential maintenance, pH regulation, cell proliferation, and adaptation to environmental changes including osmoregulation. During its life cycle, the parasite encounters extreme fluctuations in ionic concentrations, osmolarities and pHs. Previous studies in our laboratory suggested that in T. cruzi, K+ channels are important components of the regulatory mechanisms that maintain the plasma membrane potential, intracellular pH and osmolarity. It has also been demonstrated that trypomastigotes, the infective forms of the parasite, are particularly sensitive to changes in extracellular K+ concentration while epimastigotes and amastigotes are less responsive to this ion. In T. cruzi, we have identified sequences encoding for putative inward rectifier (TcKir) and calcium-activated K+ channels (TcCAKC). They have conserved functional domains, but limited identity with human homologs (<15%) making them potential selective pharmacological targets against the parasite. We propose that ion channels play an important role in sensing and adaptation to environmental conditions in T. cruzi. We propose that different types of K+ channels integrate a homeostatic network that allows the parasite to detect and respond to changes in osmotic and ionic conditions. Fundamental processes like differentiation and invasion can be regulated by modification of the ionic concentrations determining the success of the parasite in infecting new hosts. Analysis of T. cruzi potassium channels expression profiles and localization, complemented with electrophysiological studies will shed light about how these proteins work. Genetic manipulation of the level of expression and phenotypic analysis in vivo will demonstrate the physiological role of potassium channels in the parasite and will help to establish their potential as therapeutic targets.

摘要恰加斯病是一种热带人畜共患病，由原生动物寄生虫克氏锥虫引起。它在拉丁美洲流行，是世界上充血性心力衰竭的主要原因之一。从历史上看与农村地区的贫困相联系，移民和重新安置病媒正在改变流行病。美国的病例数量大幅增加就证明了这一点。治疗是仅限于硝呋莫司和苯硝唑，这两种药物的毒性都相对较大，疗效有限，而且由FDA批准。我们实验室一直致力于寻找合理的化疗方法。对于恰加斯病，它可以选择性地针对寄生虫，而不会损害人类细胞。离子通道是治疗多种疾病的选择性药物的潜在靶点，因为它们负责细胞的基本功能，如质膜和线粒体膜电位的维持，pH 调节、细胞增殖和对环境变化的适应，包括渗透调节。在它的生命中在周期中，寄生虫会遇到离子浓度、渗透压和PHS的极端波动。我们实验室以前的研究表明，在克氏锥虫中，K+通道是维持质膜电位、细胞内pH和渗透压的调节机制。它有研究还表明，这种寄生虫的感染形式--锥体鞭毛虫对胞外K+浓度的变化，而上鞭毛体和无鞭毛体对该离子的反应较弱。在T.ruzi中，我们已经鉴定出编码推测的内向整流子(TcKir)和钙激活的K+的序列频道(TcCAKC)。它们具有保守的功能结构域，但与人类同源物的同源性有限 (&lt；15%)使它们成为对抗寄生虫的潜在选择性药理靶点。我们提出了离子通道在感知和适应环境条件方面起着重要作用。我们建议不同类型的K+通道整合了一个动态平衡网络，允许寄生虫检测和对渗透和离子条件的变化作出反应。分化和入侵等基本过程可以通过改变决定寄生虫感染成功的离子浓度来调节新主人。克鲁兹毛滴虫钾通道表达谱及定位分析电生理学研究将阐明这些蛋白质是如何工作的。基因操作的水平在体内的表达和表型分析将证明钾通道在心肌细胞中的生理作用。并将有助于确定其作为治疗靶点的潜力。