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

• 批准号: 7652365
• 负责人: LESLY A TEMESVARI
• 金额: $ 21.85万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652365
• 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; 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; Lead; Lectin; Ligand Binding; Lipid Binding; Lipids; Liver Abscess; Membrane; Membrane Microdomains; Morbidity - disease rate; Nature; Oral; Organ; Parasites; Parasitic Diseases; Pathogenicity; Phagocytosis; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Play; Proteins; Public Health; Recruitment Activity; Regulation; Research Personnel; Resistance; Role; Running; Signal Pathway; Signal Transduction; Signaling Molecule; Sphingolipids; Sucrose; System; Testing; Therapeutic; 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

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（由申请方提供）：溶组织内阿米巴是阿米巴痢疾和肝脓肿的病原体。它在世界范围内的致病原因中排名第三，并被列为B类生物恐怖主义制剂。因此，有更高的优先级，以了解这种病原体的生物学和开发创新的检测和治疗策略。E.溶组织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，这些细胞外成分触发信号级联的寄生虫，导致毒力的变化。随着在大肠杆菌中发现信号通路组分的速度加快，histolytica，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），沿着肌动蛋白细胞骨架和磷酸肌醇（Pis），将质膜中的信号传导事件区室化。最近，E.溶组织细胞显示具有筏状质膜结构域。筏与一种重要的信号/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E.溶组织剂在本研究中，E. histolytica脂筏，以及几个PI，将探讨。在第一个目标中，筏和肌动蛋白之间的关系，以及它们在毒力中的作用将被检查。在第二个目标，脂筏，囊泡运输，肌动蛋白之间的连接将利用遗传方法与突变体，其中这些细胞成分是解偶联的评估。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，这些研究将有助于理解E.溶组织剂公共卫生描述：溶组织内阿米巴是阿米巴痢疾和肝脓肿的病原体，在世界上因寄生虫病死亡的人数中排名第三。由于它也被归类为生物恐怖主义制剂，因此了解其毒力的优先程度更高。拟议的研究将检查寄生虫-宿主相互作用期间激活的信号通路。由于信号可能调节毒力，这些研究将有助于理解E。溶组织剂