Basement membranes have many features, which greatly influence cell function including specific proteins and functional groups, a reservior of growth factor and other trophic agents, and a complex three dimensional topography into which adherent cells extend processes, and to which cells form adhesion plaques. The three-dimensional topography of the underlying substrate, independent of specific receptor-ligand interactions, has been recently shown to influence fundamental cell behaviors. The majority of studies conducted to date have evaluated the effect of large scale (>1 micron) features on cell behavior. The relevance of these """"""""large-scale"""""""" studies to cell behavior in vivo is not clear since our laboratories have shown basement membranes in non-vascular tissues to consist of a complex 3-dimensional nanoscale (1 micron feature size) architecture which dramatically amplifies its surface area for cell-membrane interaction. The overall purpose of this proposal is to to determine the topographic features of the basement membrane underlying the vascular endothelium and to investigate the cellular consequences of nanoscale (< 1 micron) topographic features present on the substratum. In this application, a multi-disciplinary approach is proposed to test 3 hypotheses using quantitative morphologic techniques, in vitro methodologies in cell biology, molecular biology, and state-of-the-art nanoscale fabrication techniques. Hypothesis 1: The topographic features of vascular endothelial basement membranes is similar between vessel types and locations and similar to that found for other basement membranes throughout the body. Hypothesis 2: Totally synthetic surfaces can be engineered through controlled fabrication with biologically relevant feature types, dimensions and distributions that will modulate vascular endothelial behaviors. Hypothesis 3:The topographic features of the basement membrane provide extracellular cues leading to signaling through proteins involved in focal adhesion complexes.
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