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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/19321

Title: Polarity Control in Migrating Vascular Smooth Muscle Cells: N-cadherin Localization and Function
Authors: Sabatini, Peter Jarrod Bruno
Advisor: Bendeck, Michelle
Department: Laboratory Medicine and Pathobiology
Keywords: Vascular Biology
Polarity
N-cadherin
Restenosis
Migration
Issue Date: 9-Mar-2010
Abstract: Vascular endothelial cell loss initiates directional migration of medial smooth muscle cells into the arterial intima contributing to in-stent restenosis, atherosclerosis and coronary arterial by-pass graft failure. N-cadherin is a cell-cell adhesion molecule that mediates the interaction between vascular endothelial cells and the innermost smooth muscle cells to stabilize the arterial wall. Upon injury, I reasoned that relocalization of N-cadherin on the inner most smooth muscle cells to the posterior-lateral borders stimulates cell polarization to enable directional migration. Using an in vitro scratch-wound model to stimulate cell polarity and locally remove cell-cell contacts at one pole of smooth muscle cells, I found that N-cadherin localization provides signaling cues via a Cdc42/GSK pathway that promote polarized reorganization of the cytoskeleton and directional cell migration. I also found that N-cadherin was important to functions of lamellipodia at the anterior of migrating cells. In lamellipodia, actin polymerization drives protrusion of the leading edge and coincident, but more posterior, actin depolymerization results in retrograde flow of actin and associated plasma membrane structures. Using live cell imaging, I found that clusters of N-cadherin-GFP repeatedly accumulated at the leading edge specifically at the neck of large pinocytotic vesicles called macropinosomes that were internalized and transported away from the leading edge. This localization is consistent with a role for N-cadherin in closure and scission of vesicles during macropinocytosis. These are the first studies to examine polarity in migrating vascular smooth muscle cells, and advance our understanding concerning cell-cell adhesions in controlling directional cell migration. My results suggest that N-cadherin may serve as a viable target for the treatment of arterial stenosis that would limit smooth muscle cell migration and stabilize the arterial wall. Furthermore, I report on a novel localization and function of N-cadherin in the biogenesis of macropinosomes in the lamellipodia that contribute to cell protrusion.
URI: http://hdl.handle.net/1807/19321
Appears in Collections:Doctoral
Department of Laboratory Medicine and Pathobiology - Doctoral theses

Files in This Item:

File Description SizeFormat
Movie_2.1_Phase_Contrast_Control.aviMovie 2.120.59 MB.avi. Microsoft Media PlayerView/Open
Movie_2.2_Phase_Contrast_NCadAb.aviMovie 2.219.99 MB.avi. Microsoft Media PlayerView/Open
Movie_4.1_NcadCTxB_control.aviMovie 4.13.1 MB.avi. Microsoft Media PlayerView/Open
Movie_4.2_CTxB_control.aviMovie 4.24.19 MB.avi. Microsoft Media PlayerView/Open
Movie_4.3_NcadCTxB_NcadAb.aviMovie 4.32.99 MB.avi. Microsoft Media PlayerView/Open
Movie_4.4_CTxB_NCadAb.aviMovie 4.42.64 MB.avi. Microsoft Media PlayerView/Open
Movie_4.5_actin_control.aviMovie 4.54.38 MB.avi. Microsoft Media PlayerView/Open
Movie_4.6_actin_NcadAb.aviMovie 4.65.18 MB.avi. Microsoft Media PlayerView/Open
Movie_4.7_ACAM_CTxB_coated beads.aviMovie 4.72.19 MB.avi. Microsoft Media PlayerView/Open
Movie_4.8_Confocal_NcadGFP.aviMovie 4.89.51 MB.avi. Microsoft Media PlayerView/Open
Sabatini_Peter_JB_200904_PhD_thesis.pdfThesis131.28 MBAdobe PDF
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