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Identification and function of mechanosensitive channels in Trypanosoma cruzi

克氏锥虫机械敏感通道的鉴定和功能

基本信息

批准号：
10730514
负责人：
Veronica Jimenez
金额：
$ 41.66万
依托单位：
CALIFORNIA STATE UNIVERSITY FULLERTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-19 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730514
关键词：
Ablation Affect Automobile Driving Benznidazole Biochemical Biological Blood Vessels CRISPR/Cas technology Cations Cell Differentiation process Cell Volumes Cell membrane Cells Chagas Disease Code Complement Complex Congestive Heart Failure Development Disease Drug Targeting Electrophysiology (science)Endemic Diseases Environment Epidemiology Etiology Genes Genetic Genome Goals Growth Heart Diseases Homologous Gene Immigration Impairment In Vitro Individual Integral Membrane Protein Invaded Knock-out Latin America Life Life Cycle Stages Light Link Lipid Bilayers Lipids Mammalian Cell Mechanics Mediating Membrane Membrane Proteins Methods Molecular Nifurtimox Organism Osmoregulation Osmosis Parasites Pathology Pattern Permeability Pharmaceutical Preparations Phenotype Physiological Piezo ion channels Play Poverty Process Property Proteins Regulation Role Signal Pathway Spheroplasts Stimulus Stress Stretching System Temperature Testing Trypanosoma cruzi Vacuole Variant Virulence Work Zoonoses biophysical properties cancer cell cell motility cell type differential expression environmental change extracellular fitness gain of function genetic manipulation in silico in vivo loss of function migration mutant new therapeutic target overexpression pathogen pathogenic bacteria pharmacologic proteoliposomes quorum sensing response rural area sensor shear stress stem cell differentiation success therapeutic target trait transcriptomics vector

项目摘要

Abstract Chagas disease is a zoonotic tropical pathology, caused by the protozoan parasite Trypanosoma cruzi. Endemic in 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 for general use. The study of the mechanisms of sensing, adaptation and survival of the parasite is important for the identification of selective drug targets that can lead to the elimination of the parasite without affecting the host cells. During the transformation into different life stages, T. cruzi finds extreme fluctuations in environmental conditions to which it must adapt in order to survive. Mechanosensitive channels are cation channels able to detect changes in the tension of the membranes and are usually activated by stretch of the lipid bilayer. They are considered the primary sensors of tension changes in a multiplicity of cells and organisms, triggering signaling pathways that drive osmoregulation, shear stress sensing and differentiation. Although T. cruzi has a robust capacity to survive in various environments, the identity of the molecules detecting changes and eliciting adaptive responses in the parasites is still unknown. Previous in silico studies suggest the presence of several putative mechanosensitive channels in T. cruzi. We are focusing our work in two types of proteins: TcMscS, a channel with structural features shared by bacterial small conductance mechanosensitive channels; and Piezo channels, large proteins that regulate functions such as cell volume, shear stress sensing and motility. We propose that mechanically activated channels play an important role in sensing and adaptation to environmental conditions in T. cruzi, determining the success of the host cell invasion and the survival of the parasite. Analysis of T. cruzi mechanosensitive channels expression profiles and localization, complemented with electrophysiological studies will shed light about the mechanism of activation and modulation of these proteins. Additionally, we will explore the activation of signaling pathways linked to the activation of the channels. Genetic manipulation of the level of expression and phenotypic analysis in vivo will demonstrate the physiological role of TcMscS and TcPiezo channels in the parasites and will help establishing 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，是世界上导致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。治疗受到限制对硝呋莫司和苯硝唑来说，这两种药物的毒性都比较大，疗效有限，没有得到美国食品及药物管理局为一般用途。对寄生虫的感知、适应和生存机制的研究对人类健康具有重要意义。识别可在不影响宿主的情况下消除寄生虫的选择性药物靶点细胞。在转变为不同的生命阶段期间，T.Cruzi发现环境中的极端波动为了生存，它必须适应的条件。机械敏感通道是阳离子通道，能够检测膜张力的变化，通常由脂双层的拉伸激活。他们被认为是多种细胞和生物体中张力变化的主要传感器，触发驱动渗透调节、剪切力感应和分化的信号通路。尽管克氏锥虫有一种在各种环境中生存的强大能力，检测变化和引发变化的分子的身份寄生虫的适应性反应仍不清楚。以前的硅胶研究表明，有几个克氏锥虫中可能存在的机械敏感通道。我们的工作集中在两种蛋白质上：TcMscS，一种具有细菌小电导机械敏感通道共同结构特征的通道；以及Piezo 通道是调节细胞体积、剪切力感应和运动等功能的大型蛋白质。我们认为，机械激活的通道在感知和适应克氏锥虫的环境条件，决定了宿主细胞入侵的成功和宿主细胞的存活寄生虫。克氏锥虫机械敏感通道表达谱分析及定位补充电生理学研究将有助于阐明这些神经元的激活和调节机制蛋白质。此外，我们还将探索与通道激活相关的信号通路的激活。基因操作的表达水平和体内表型分析将证明生理学 TcMscS和TcPiezo通道在寄生虫中的作用将有助于建立它们的治疗潜力目标。