Cadherin-independent epithelial formation

不依赖钙粘蛋白的上皮形成

• 批准号: 8190790
• 负责人: Susan E Mango
• 金额: $ 25.2万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190790
• 关键词: ATP phosphohydrolase; Adherens Junction; Adhesions; Apical; Applications Grants; Area; Binding; Biological Models; Cadherins; Caenorhabditis elegans; Cell Polarity; Cell division; Cell surface; Cells; Complement; Cues; Cytokinesis; Cytoplasm; Cytoskeleton; Data; Defect; Development; Drosophila genus; E-Cadherin; Epidermis; Epithelial; Epithelial Cells; Epithelium; Event; Family; Funding Mechanisms; Gases; Genetic; Genetic Screening; Goals; Image; In Vitro; Integrins; Kinesin; Letters; Link; Lipids; Liquid substance; Literature; Location; Mediating; Mesenchymal; Microtubules; Modeling; Molecular Genetics; Motor; Mutation; Organ; Organelles; Organism; Pathway interactions; Phenotype; Phosphatidylinositols; Positioning Attribute; Process; Research; Role; Signal Transduction; Staging; Structure; System; Testing; Tissues; Tube; Vertebrates; Work; cell cortex; daughter cell; epithelial to mesenchymal transition; genetic analysis; in vivo; mutant; novel; protein E; protein distribution; research study; rho; tissue culture

DESCRIPTION (provided by applicant): The goal of this grant proposal is to initiate a new area of research that will investigate novel pathways of epithelium formation. Epithelia perform a vital function to keep tissues, organs and cells in distinct topological compartments. For example, sheets of epithelia line organs, epithelial tubes transport liquids and gases throughout the body. Classic experiments established the paradigm that the adhesion protein E-cadherin and its partners 1-catenin and 2-catenin initiate polarity during epithelium formation. More recent work using 3D culture systems has implicated integrins and phosphoinositides as polarizing cues to create epithelia. These studies relied on tissue culture models that can be induced to form epithelial structures in vitro or on genetic organisms, predominantly Drosophila. Our aim is to complement the classical approaches with a new genetic system for epithelium development. The C. elegans arcade cells undergo a mesenchymal to epithelial transition, and the resulting epithelial tube links the gut to the exterior epidermis. The impetus for our new project is the observation that C. elegans generates this epithelium (and its other epithelia) independent of known epithelial regulators including cadherins, catenins or integrins. We hypothesize that the C. elegans arcade cells rely on an alternative pathway to build epithelia, one that is amenable to genetic analyses and in vivo imaging. We will analyze the MKLP kinesin zen-4 during epithelium formation. We previously showed that inactivation of zen-4 blocks epithelium formation of the arcade cells, the strongest epithelial defect yet observed in C. elegans. We will analyze ZEN-4 and its role in epithelia, as an entry point towards understanding non-canonical epithelium formation. These experiments will establish the C. elegans arcade cells as a model for epithelium formation, and will set the stage for understanding non-canonical epithelium formation. PUBLIC HEALTH RELEVANCE: Epithelia are composed of highly polarized, adherent cells with an asymmetric distribution of proteins, lipids and organelles within the cytoplasm and at the cell surface. Epithelia perform a vital function to keep tissues, organs and cells in distinct topological compartments. This proposal seeks to establish a new model system to study epithelium formation, one that will uncover non-classical pathways for polarity and epithelialization. )

描述（由申请人提供）：该拨款提案的目标是启动一个新的研究领域，将调查上皮形成的新途径。上皮细胞在维持组织、器官和细胞处于不同的拓扑分区中起着重要作用。例如，上皮细胞层、上皮管在整个身体中运输液体和气体。经典实验建立了粘附蛋白E-钙粘蛋白及其伴侣1-连环蛋白和2-连环蛋白在上皮形成期间启动极性的范例。最近使用3D培养系统的工作涉及整合素和磷酸肌醇作为产生上皮细胞的极化线索。这些研究依赖于可以在体外诱导形成上皮结构的组织培养模型或遗传生物，主要是果蝇。我们的目标是补充经典的方法与一个新的遗传系统的上皮细胞的发展。梭线虫拱廊细胞经历间充质到上皮的转变，并且所产生的上皮管将肠连接到外表皮。我们新项目的动力是观察到C。秀丽线虫不依赖于已知的上皮调节剂（包括钙粘蛋白、连环蛋白或整联蛋白）产生这种上皮（及其其它上皮）。我们假设C.秀丽线虫拱廊细胞依赖于另一种途径来建立上皮，这种途径适合于遗传分析和体内成像。我们将分析上皮形成过程中的MKLP驱动蛋白zen-4。我们先前发现zen-4的失活阻断了拱状细胞的上皮形成，拱状细胞是在C.优雅的我们将分析ZEN-4及其在上皮中的作用，作为理解非典型上皮形成的切入点。这些实验将建立C. elegans arcade细胞作为上皮形成的模型，并将为理解非典型上皮形成奠定基础。 公共卫生关系：上皮细胞由高度极化的贴壁细胞组成，细胞质内和细胞表面的蛋白质、脂质和细胞器分布不对称。上皮细胞在维持组织、器官和细胞处于不同的拓扑分区中起着重要作用。该提案旨在建立一个新的模型系统来研究上皮形成，这将揭示极性和上皮形成的非经典途径。)