Document text
Principal Investigator: MATTHEW C GIBSON
Organization: STOWERS INSTITUTE FOR MEDICAL RESEARCH
Fiscal Year: 2019
Award: $290,400
Funding agency: National Institute of General Medical Sciences
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.
Terms: <Abnormal Cell><Actin-Activated ATPase><Actins><Address><Adopted><Animal Model><Animal Models and Related Studies><Animals><Apical><Architecture><Area><Assay><Autoregulation><Basal Cell><Bioassay><Biochemical><Biologic Assays><Biological Assay><Biology><Body Tissues><Cancer Treatment><Cancers><Carcinoma><Cell Body><Cell Function><Cell Growth in Number><Cell Junctions><Cell Multiplication><Cell Polarity><Cell Process><Cell Proliferation><Cell division><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cellular biology><Complex><Data><Defect><Development><Disease><Disorder><Disseminated Malignant Neoplasm><Drosophila><Drosophila genus><Early Diagnosis><Early treatment><Elements><Engineering / Architecture><Epithelial><Epithelial Cell Proliferation><Epithelial Cells><Epithelial cancer><Epithelium><Epithelium Part><Event><Experimental Models><Foundations><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genetic><Genetic Models><Genetic analyses><Homeostasis><Human><Image><Intercellular Junctions><Interphase><Knowledge><Lead><M Phase><Maintenance><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mammalia><Mammals><Mesenchymas><Mesenchyme><Metaphase><Metastatic Cancer><Metastatic Malignant Neoplasm><Mitosis><Mitosis Stage><Mitotic><Mitotic Metaphase><Mitotic spindle><Modeling><Modern Man><Molecular><Molecular Genetics><Morphogenesis><Morphology><Myosin ATPase><Myosin Adenosine Triphosphatase><Myosin Adenosinetriphosphatase><Myosins><Organ><Pathogenesis><Pathologic Processes><Pathological Processes><Pathology><Pathway interactions><Pb element><Phenotype><Physiological Homeostasis><Physiology><Process><Proliferating><Prophase><Proteins><Proteomics><Rho-associated kinase><Rho-kinase><Role><SH2 Domains><Site><Structure><Study models><Subcellular Process><Surface><System><Testing><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Tumor Suppressor Proteins><anti-cancer therapy><anticancer therapy><cancer therapy><cell biology><cellular polarity><developmental><early detection><early therapy><epithelial carcinoma><epithelial to mesenchymal transition><experiment><experimental research><experimental study><fruit fly><gene expression analysis><gene expression assay><genetic analysis><heavy metal Pb><heavy metal lead><human disease><image-based method><imaginal disc><imaging><imaging method><imaging modality><imaging study><in vivo><in vivo Model><innovate><innovation><innovative><insight><malignancy><membrane-organizing extension spike protein><model of animal><model organism><moesin><monolayer><neoplasm/cancer><neoplastic><novel><pathway><polarized cell><public health relevance><social role><src Homology Region 2 Domain><transcriptional profiling><tumor><tumor suppressor>