Role of lipid rafts and phosphoinositides in E. histolytica virulence

脂筏和磷酸肌醇在溶组织内阿米巴毒力中的作用

基本信息

批准号：
7317969
负责人：
LESLY A TEMESVARI
金额：
$ 22.13万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-12-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7317969
关键词：
1-Phosphatidylinositol 3-Kinase Acetylgalactosamine Actins Address Adhesions Amebiasis Amebic colitis Biological Biology Biosensor Bioterrorism Categories Cell Adhesion Molecules Cell Line Cell membrane Cells Cellular biology Cessation of life Cholesterol Class Colitis Cyst Cytoskeleton DNA Sequence Rearrangement Data Density Gradient Centrifugation Detection Detergents Developed Countries Developing Countries Disease Dominant-Negative Mutation Drug Design Entamoeba histolytica Environment Enzymes Epithelium Epitopes Erythrophagocytosis Eukaryota Eukaryotic Cell Event Funding Gal-GalNAc Galactose Gene Expression Genetic Guanosine Triphosphate Phosphohydrolases Homologous Gene Human Infection Invasive Lead Lectin Ligand Binding Lipid Binding Lipids Liver Abscess Localized Membrane Membrane Microdomains Morbidity - disease rate Nature Oral Organ Parasites Parasitic Diseases Pathogenicity Phagocytosis Phosphatidylinositols Phosphoric Monoester Hydrolases Play Proteins Public Health Rate Recruitment Activity Regulation Research Personnel Resistance Role Running Signal Pathway Signal Transduction Signaling Molecule Sphingolipids Sucrose System Testing Therapeutic Thinking Time Vaccines Vesicle Virulence base extracellular innovation insight macromolecule mutant novel pathogen phosphatidylinositol 3-phosphate prevent programs protein function rab GTP-Binding Proteins tensin trafficking

项目摘要

DESCRIPTION (provided by applicant): Entamoeba histolytica is the causative agent of amoebic dysentery and liver abscess. It ranks third as a worldwide cause of morbidity and has been classified as a Category B bioterrorism agent. Therefore, there is elevated priority to understand the biology of and develop innovative detection and therapeutic strategies for this pathogen. E. histolytica trophozoites will encounter a variety of host cells and macromolecules during infection. It is postulated that these extracellular components trigger signaling cascades in the parasite that lead to changes in virulence. With the rate at which the components of signaling pathways are being discovered in E. histolytica, the new challenge is to understand the temporal and spatial regulation of signaling events in these cells. In other eukaryotes, lipid rafts (cholesterol- and sphingolipid-rich plasma membrane domains), along with the actin cytoskeleton, and phosphoinositides (Pis), compartmentalize signaling events in the plasma membrane. Recently, E. histolytica cells were shown to possess raft-like plasma membrane domains. The co-localization of rafts with an important signaling/adhesion molecule, the galactose/N-acetylgalactosamine (Gal/GalNAc) lectin, suggests that rafts may also participate in signaling in E. histolytica. In the proposed studies, the biological role of E. histolytica lipid rafts, as well as of several Pis, will be explored. In the first Aim, the relationship between rafts and actin, and their role in virulence will be examined. In the second Aim, the connection between lipid rafts, vesicle trafficking, and actin will be assessed utilizing genetic approaches with mutants in which these cellular components are uncoupled. Finally, in the third Aim, the role of Pis in parasite virulence functions will be examined. This will be achieved by examining the function of PI 3-kinase and PTEN phosphatase, enzymes with complimentary roles in Pi- based signaling. Since vesicle trafficking, actin cytoskeletal rearrangements and signaling likely regulate virulence; these studies will contribute significantly to understanding the pathogenicity of E. histolytica. Public Health Description: Entamoeba histolytica is the causitive agent of amoebic dysentery and liver abscess and ranks third in the world for deaths due to parasitic disease. Since it is also classified as a bioterrorism agent, there is elevated priority to understand its virulence. The proposed studies will examine signaling pathways that are activated during parasite-host interaction. Since signaling likely regulates virulence, these studies will contribute significantly to understanding the biology of E. histolytica.

描述（由申请人提供）：溶组织内阿米巴是阿米巴痢疾和肝脓肿的病原体。它在全球发病原因中排名第三，并被列为 B 类生物恐怖主义制剂。因此，了解这种病原体的生物学并开发创新的检测和治疗策略是当务之急。溶组织内阿米巴滋养体在感染过程中会遇到多种宿主细胞和大分子。据推测，这些细胞外成分会触发寄生虫中的信号级联，从而导致毒力发生变化。随着在溶组织内阿米巴中发现信号通路成分的速度加快，新的挑战是了解这些细胞中信号事件的时间和空间调节。在其他真核生物中，脂筏（富含胆固醇和鞘脂的质膜结构域）与肌动蛋白细胞骨架和磷酸肌醇 (Pis) 一起划分质膜中的信号传导事件。最近，溶组织内阿米巴细胞被证明具有筏状质膜结构域。筏与重要的信号/粘附分子半乳糖/N-乙酰半乳糖胺（Gal/GalNAc）凝集素的共定位表明，筏也可能参与溶组织内阿米巴的信号传导。在拟议的研究中，将探讨溶组织内阿米巴脂筏以及几种 Pi 的生物学作用。在第一个目标中，将研究筏和肌动蛋白之间的关系以及它们在毒力中的作用。在第二个目标中，将利用遗传方法和突变体来评估脂筏、囊泡运输和肌动蛋白之间的联系，其中这些细胞成分是解偶联的。最后，在第三个目标中，将研究 Pis 在寄生虫毒力功能中的作用。这将通过检查 PI 3 激酶和 PTEN 磷酸酶的功能来实现，这两种酶在基于 Pi 的信号传导中具有互补作用。由于囊泡运输、肌动蛋白细胞骨架重排和信号传导可能调节毒力；这些研究将极大地有助于了解溶组织内阿米巴的致病性。公共卫生描述：溶组织内阿米巴是阿米巴痢疾和肝脓肿的病原体，在寄生虫病死亡人数中排名世界第三。由于它也被归类为生物恐怖主义制剂，因此优先了解其毒力。拟议的研究将检查寄生虫与宿主相互作用期间激活的信号通路。由于信号传导可能调节毒力，这些研究将极大地有助于了解溶组织内阿米巴的生物学。