The broad long-term objective of this project is to develop computational models to gain a quantitative understanding of angiogenesis in skeletal muscle in response to exercise or to administration of exogenous growth factors. Experimental data are available that include measurements of expression of vascular endothelial growth factor (VEGF) and its receptors, and of metalloproteinases (MMP) during and following muscle stimulation. Several key processes of angiogenesis in rat and human skeletal muscle will be studied using computational modeling. Models will be based on principles of biochemical kinetics and mass transport.
Specific Aim 1 will quantify the dynamics of VEGF interactions with its receptors during and following stimulation in rat muscles. A novel molecular-level model will be formulated that will include major VEGF isoforms, their endothelial cell high-affinity receptors VEGFR1 and VEGFR2, neuropilins, and heparan sulfate proteoglycans at the cell surface and in the basement membrane and extracellular matrix.
Specific Aim 2 will analyze important aspects of capillary sprout formation by describing the proteolytic degradation of the basement membrane on the pre-existing microvessels and of the extracellular matrix. Models will include collagen, MMPs, membrane-type metalloproteinases, tissue inhibitor of metalloproteinases and other macro-molecules.
In Specific Aim 3 the models will be applied to human muscle under physiological exercise and under conditions of exogenous administration of VEGF and its homolog, placenta! growth factor (PIGF). In therapeutic angiogenesis for peripheral vascular disease, intravascular or intramuscular administration of VEGF have been studied extensively in recent years, but the quantitative understanding of these procedures is incomplete. This research will provide a quantitative description of important processes leading to signal transduction events and neovascularization. It will have an impact on understanding both basic mechanisms of angiogenesis and therapeutic applications in peripheral vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL079653-01
Application #
6873154
Study Section
Special Emphasis Panel (ZRG1-MABS (01))
Program Officer
Goldman, Stephen
Project Start
2005-02-01
Project End
2010-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
1
Fiscal Year
2005
Total Cost
$284,157
Indirect Cost
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Liu, Gang; Qutub, Amina A; Vempati, Prakash et al. (2011) Module-based multiscale simulation of angiogenesis in skeletal muscle. Theor Biol Med Model 8:6
Imoukhuede, P I; Popel, Aleksander S (2011) Quantification and cell-to-cell variation of vascular endothelial growth factor receptors. Exp Cell Res 317:955-65
Wu, Florence T H; Stefanini, Marianne O; Mac Gabhann, Feilim et al. (2010) A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use. J Cell Mol Med 14:528-52
Wu, Florence T H; Stefanini, Marianne O; Mac Gabhann, Feilim et al. (2010) VEGF and soluble VEGF receptor-1 (sFlt-1) distributions in peripheral arterial disease: an in silico model. Am J Physiol Heart Circ Physiol 298:H2174-91
Wu, Florence T H; Stefanini, Marianne O; Mac Gabhann, Feilim et al. (2009) Modeling of growth factor-receptor systems from molecular-level protein interaction networks to whole-body compartment models. Methods Enzymol 467:461-97
Qutub, Amina A; Mac Gabhann, Feilim; Karagiannis, Emmanouil D et al. (2009) Multiscale models of angiogenesis. IEEE Eng Med Biol Mag 28:14-31
Wu, Florence T H; Stefanini, Marianne O; Mac Gabhann, Feilim et al. (2009) A compartment model of VEGF distribution in humans in the presence of soluble VEGF receptor-1 acting as a ligand trap. PLoS One 4:e5108
Wu, Florence T H; Stefanini, Marianne O; Mac Gabhann, Feilim et al. (2009) Computational kinetic model of VEGF trapping by soluble VEGF receptor-1: effects of transendothelial and lymphatic macromolecular transport. Physiol Genomics 38:29-41
Qutub, Amina A; Liu, Gang; Vempati, Prakash et al. (2009) Integration of angiogenesis modules at multiple scales: from molecular to tissue. Pac Symp Biocomput :316-27
Stefanini, Marianne O; Wu, Florence T H; Mac Gabhann, Feilim et al. (2009) The presence of VEGF receptors on the luminal surface of endothelial cells affects VEGF distribution and VEGF signaling. PLoS Comput Biol 5:e1000622

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