Mitotic Rounding and Planar Spindle Alignment in Proliferating Epithelia

增殖上皮细胞的有丝分裂圆化和平面纺锤体排列

• 批准号: 8962441
• 负责人: MATTHEW C GIBSON
• 金额: $ 29.04万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962441
• 关键词: 14-3-3 Proteins; Abnormal Cell; Actins; Address; Adopted; Animal Model; Animals; Apical; Architecture; Area; Biochemical; Biological Assay; Biology; Carcinoma; Cell Polarity; Cell Proliferation; Cell division; Cell physiology; Cells; Cellular biology; Complex; Data; Defect; Development; Disease; Disseminated Malignant Neoplasm; Drosophila genus; Early Diagnosis; Early treatment; Elements; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Event; Experimental Models; Foundations; Genetic; Genetic Models; Homeostasis; Human; Image; Intercellular Junctions; Interphase; Knowledge; Lead; Life; Maintenance; Malignant Neoplasms; Mammals; Mesenchyme; Metaphase; Mitosis; Mitotic; Mitotic spindle; Modeling; Molecular; Molecular Genetics; Morphogenesis; Morphology; Myosin ATPase; Organ; Pathogenesis; Pathologic Processes; Pathology; Pathway interactions; Physiology; Process; Proliferating; Prophase; Proteins; Proteomics; Rho-associated kinase; Role; Site; Structure; Surface; System; Testing; Tissues; Tumor Suppressor Proteins; base; epithelial to mesenchymal transition; genetic analysis; genetic profiling; human disease; imaginal disc; imaging modality; in vivo; in vivo Model; innovation; insight; moesin; monolayer; neoplastic; novel; polarized cell; public health relevance; research study; src Homology Region 2 Domain; tumor

 DESCRIPTION (provided by applicant): Mitotic Rounding and Planar Spindle Alignment in Proliferating Epithelia Project Summary During development and homeostasis of multicellular animals, adherent layers of proliferating epithelial cells provide the spatial and structural contet essential for nearly all aspects of organ morphogenesis and physiology. In humans, defects in the control of epithelial cell proliferation can result in a wide range of pathologies, including te approximate 80% of cancers derived from epithelia (carcinomas). Nevertheless, despite the central importance of understanding epithelial proliferation in development and disease, precisely how mitotic division is spatially and temporally coordinated with the maintenance of epithelial architecture remains poorly understood. In this proposal, we take advantage of Drosophila imaginal discs as a genetic model to uncover fundamental molecular and cellular mechanisms that coordinate cell proliferation with epithelial apico-basal polarization in vivo. In Aim 1 we use genetic analysis and innovative live imaging methods to investigate how mitotic epithelial cells disassemble their complex interphase morphologies at prophase entry and subsequently round up at the apical epithelial surface. In Aim 2 we use genetic, biochemical, and proteomic approaches to interrogate interactions between the mitotic spindle poles and the junction-localized tumor suppressors Scribble and Discs Large during planar spindle alignment in vivo. Lastly, in Aim 3 we investigate the molecular and cellular features of epithelial-to-mesenchymal transitions (EMTs) that result from defective planar orientation of the mitotic spindle during epithelial cell division. At the conclusion of these studies, we will have greatly expanded our fundamental knowledge of epithelial cell division and planar spindle orientation developed a novel genetically-tractable model for abnormal EMT events that result from defective spindle orientation in vivo, and provided detailed mechanistic insight into the molecular genetic control of both of these processes.

 描述（由申请人提供）：有丝分裂圆化和平面纺锤体排列在增殖上皮中的项目摘要在多细胞动物的发育和体内平衡过程中，增殖上皮细胞的粘附层为器官形态发生和生理学的几乎所有方面提供了空间和结构上的必需。在人类中，上皮细胞增殖控制的缺陷可导致广泛的病理学，包括约80%的源自上皮的癌症（癌）。然而，尽管了解上皮细胞增殖在发育和疾病中的重要性，但有丝分裂如何在空间和时间上与上皮结构的维持协调仍然知之甚少。在这个建议中，我们利用果蝇成虫盘作为遗传模型，以揭示基本的分子和细胞机制，协调细胞增殖与上皮apico-basal极化在体内。在目的1中，我们使用遗传分析和创新的实时成像方法来研究有丝分裂上皮细胞如何在前期进入时分解其复杂的间期形态，并随后在顶端上皮表面聚集。在目的2中，我们使用遗传，生物化学和蛋白质组学的方法来询问有丝分裂纺锤体极和连接定位的肿瘤抑制因子Scribble和光盘大平面纺锤体对齐过程中在体内的相互作用。最后，在目标3中，我们研究了上皮细胞分裂过程中有丝分裂纺锤体平面方向缺陷导致的上皮细胞向间充质转化（EMT）的分子和细胞特征。在这些研究的结论中，我们将极大地扩展我们对上皮细胞分裂和平面纺锤体取向的基础知识，开发出一种新的遗传学上易于处理的模型，用于体内由纺锤体取向缺陷引起的异常EMT事件，并提供了对分子机制的详细见解。 这两个过程的遗传控制。