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Epithelial apical membrane polarization, morphogenesis, and regulation of gene expression

Reference	BB/X000575/1
Principal Investigator / Supervisor	Professor Karl Matter
Co-Investigators / Co-Supervisors	Professor James Bainbridge, Professor Maria Balda
Institution	University College London
Department	Institute of Ophthalmology
Funding type	Research
Value (£)	692,791
Status	Current
Type	Research Grant
Start date	23/01/2023
End date	22/01/2026
Duration	36 months

Abstract

Coordination of cell adhesion, polarisation, and gene expression drives epithelial morphogenesis and maintenance. Disruption of these processes leads to epithelial malfunction, degeneration, and disease. Here, we propose to investigate the crosstalk between cell polarization, adhesion, and gene expression and its importance in regulating epithelial tissue behaviour and homeostasis in vitro and in vivo. We have discovered an evolutionarily conserved Cdc42 signalling mechanism that drives apical cytoskeletal actomyosin activity and, thereby, morphogenetic processes and apical polarization. Based on pilot studies, the pathway coordinates cell polarisation, epithelial morphogenesis and gene expression by orchestrating cell-wide changes in cytoskeletal tension and impacting on transcriptional signalling mechanisms regulated at least in part by basolateral processes and RhoA signalling. Hence, activation of the mechanism at the apical domain may induce remodelling of mechanical forces across the cells, promoting cell polarisation and shape changes, as well as regulating expression of genes that are involved in cell proliferation and function. We propose a combination of in vitro and in vivo methods to determine how activation of apical Cdc42 signalling regulates cytoskeletal tension across epithelial cells and the importance for this mechanism in regulating epithelial cell morphogenesis, homeostasis, and gene expression in vitro and in vivo. We expect to uncover new mechanisms that underlie epithelial polarisation and morphogenesis. Such knowledge is important for our understanding of common chronic and acute diseases that affect different organs, such as infections, cancer and age-related conditions.

Summary

Epithelia are sheets of cells that line our bodies and internal surfaces such as the intestine and the kidney, as well as the front and back of the eye. A. All our organs require epithelial cells for normal functioning and, in most of them, they are the main functional cell type. For example, in the intestine they support digestion and transport of nutrients from the intestinal lumen to the underlying blood stream. In other tissues, epithelia have crucial support functions. An example is the retinal pigment epithelium at the back of the eye, which provides vital support functions for photoreceptors, the cells that sense light. Without a healthy retinal pigment epithelium, photoreceptors stop to function and die. We are interested in the processes that determine how such epithelia form and are maintained throughout life, and how deregulation of such processes leads to tissue degeneration and different types of diseases. Such knowledge is important for diseases associated with aging, in which normal tissue often function often declines due to defects in epithelia. To be able to form cell sheets and to function correctly, epithelial cells need to adhere to each other, and they need to polarize by forming distinct cell surface domains that have different compositions and functional roles. A typical epithelial cell has a basal domain with which it interacts with the underlying tissue, a lateral domain with which it adheres to its neighbours enabling sheet formation, and an apical domain that faces the outside of an epithelium. The apical and lateral domains are separated by a large protein complex called tight junctions. Tight junctions support barrier formation by making cells adhere to each other and by functioning as regulatory centres that guide cell proliferation, behaviour, polarization, and tissue formation. Defects in epithelial cell polarization occur in many serious diseases that can be inherited or induced by aging, environmental factors, or infections. Here, we are focusing on a mechanism that we have recently discovered to regulate cells polarization and cell shape. We have discovered this mechanism in cells in culture, but it is also essential in tissues as its disruption in the retinal pigment epithelium leads to malfunction and retinal degeneration. One of the main effects of the pathway is on the regulation of the cytoskeleton, a dynamic structure formed by filaments and motor proteins that generate mechanical forces. Our pilot studies suggest a model in which activation of the mechanism at the apical domain induces a signalling cascade that leads to remodelling of mechanical forces across the cell, promoting cell polarisation and shape changes, as well as regulating expression of genes that are involved in cell proliferation and function. Our first aim is to determine how this mechanism regulates mechanical forces across epithelial cells and to test the hypothesis using approaches to manipulate opposing forces. Our second aim is to determine the underlying molecular mechanisms by which this mechanism regulates cell proliferation and gene expression in cell culture models as well as the retinal pigment epithelium in mice. We expect our results to establish new principles that govern how epithelia form and how deregulation of the underlying biological mechanisms leads to tissue malfunction and disease. The expected knowledge will support the development of new approaches to repair malfunctioning tissues in acute diseases such as infections and cancer, as well as chronic and age-related diseases that affect the eye and other organs.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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