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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL079012-01A1
Application #
6985030
Study Section
Special Emphasis Panel (ZRG1-MTE (01))
Program Officer
Srinivas, Pothur R
Project Start
2005-08-15
Project End
2010-07-31
Budget Start
2005-08-15
Budget End
2006-07-31
Support Year
1
Fiscal Year
2005
Total Cost
$339,317
Indirect Cost
Name
University of Wisconsin Madison
Department
Surgery
Type
Schools of Veterinary Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Garland, Shaun P; McKee, Clayton T; Chang, Yow-Ren et al. (2014) A cell culture substrate with biologically relevant size-scale topography and compliance of the basement membrane. Langmuir 30:2101-8
Dreier, Britta; Gasiorowski, Joshua Z; Morgan, Joshua T et al. (2013) Early responses of vascular endothelial cells to topographic cues. Am J Physiol Cell Physiol 305:C290-8
Morgan, Joshua T; Wood, Joshua A; Shah, Nihar M et al. (2012) Integration of basal topographic cues and apical shear stress in vascular endothelial cells. Biomaterials 33:4126-35
McKee, Clayton T; Wood, Joshua A; Ly, Irene et al. (2012) The influence of a biologically relevant substratum topography on human aortic and umbilical vein endothelial cells. Biophys J 102:1224-33
McKee, Clayton T; Last, Julie A; Russell, Paul et al. (2011) Indentation versus tensile measurements of Young's modulus for soft biological tissues. Tissue Eng Part B Rev 17:155-64
Wood, Joshua A; Shah, Nihar M; McKee, Clayton T et al. (2011) The role of substratum compliance of hydrogels on vascular endothelial cell behavior. Biomaterials 32:5056-64
Gasiorowski, Joshua Z; Liliensiek, Sara J; Russell, Paul et al. (2010) Alterations in gene expression of human vascular endothelial cells associated with nanotopographic cues. Biomaterials 31:8882-8
Liliensiek, Sara J; Wood, Joshua A; Yong, Jiang et al. (2010) Modulation of human vascular endothelial cell behaviors by nanotopographic cues. Biomaterials 31:5418-26
Liliensiek, Sara J; Nealey, Paul; Murphy, Christopher J (2009) Characterization of endothelial basement membrane nanotopography in rhesus macaque as a guide for vessel tissue engineering. Tissue Eng Part A 15:2643-51
Gasiorowski, Joshua Z; Russell, Paul (2009) Biological properties of trabecular meshwork cells. Exp Eye Res 88:671-5

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