Wednesday, April 24, 2024
4/24/2024
Project Summary/Abstract The development and normal physiology of multicellular organisms relies on the presence and proper function of epithelial tissue. Epithelia are characterized by their organization as sheets of tightly adherent cells that are polarized along an apical-basal axis. The cellular basis to accomplish their functions is provided by their polarized architecture. Loss of this organization has significant detrimental consequences, such as developmental defects and cancer. The basement membrane (BM), a specialized sheet of the extracellular matrix, is secreted basally by epithelial cells and is a major regulator of epithelial polarity, tissue organization, and organ morphogenesis. Importantly, the loss of integrity and misregulation of the BM have been associated with carcinomas and tumor metastasis. Despite the significance of the BM in both normal and abnormal epithelial cells, the molecular mechanisms ensuring the accurate basal secretion of BM proteins remain largely elusive. The main goals of this work are to discover new components, determine their precise roles, and organize them into biological pathway(s) dedicated to the establishment and maintenance of BM polarity. This is will eventually identify attractive targets for cancer therapeutics and/or possible new readouts of treatment effectiveness. To study polarized BM deposition, we are using the follicular epithelium of the Drosophila ovary as a model system. Using the power of Drosophila genetics, along with established cellular and biochemistry techniques, we will characterize the role of different factors that we identified as critical for the proper placement of BM proteins. First, we will identify and characterize the cellular components specifically involved in the intracellular trafficking and secretion of proteins that form the BM. Then, since the intracellular trafficking of BM-containing vesicles that leads to the basal deposition of BM protein is poorly understand, we will visualize and measure it, both in fixed tissue as well as live imaging, using confocal and electron microscopy. Finally, we will uncover and characterize a signaling pathway dedicated to the basal sorting of BM proteins. Altogether, this scientific proposal will provide critical insights into the biological pathways involved in the control of BM polarity, and by extension on our understanding of the development and maintenance of the epithelial cell polarity, and into its deregulation in pathological situations such as cancer.
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