Modeling of growth factor-receptor systems from molecular-level protein interaction networks to whole-body compartment models.
Most physiological processes are subjected to molecular regulation by growth factors, which are secreted proteins that activate chemical signal transduction pathways through binding of specific cell-surface receptors. One particular growth factor system involved in the in vivo regulation of blood vessel growth is called the vascular endothelial growth factor (VEGF) system. Computational and numerical techniques are well suited to handle the molecular complexity (the number of binding partners involved, including ligands, receptors, and inert binding sites) and multiscale nature (intratissue vs. intertissue transport and local vs. systemic effects within an organism) involved in modeling growth factor system interactions and effects. This chapter introduces a variety of in silico models that seek to recapitulate different aspects of VEGF system biology at various spatial and temporal scales: molecular-level kinetic models focus on VEGF ligand-receptor interactions at and near the endothelial cell surface; mesoscale single-tissue 3D models can simulate the effects of multicellular tissue architecture on the spatial variation in VEGF ligand production and receptor activation; compartmental modeling allows efficient prediction of average interstitial VEGF concentrations and cell-surface VEGF signaling intensities across multiple large tissue volumes, permitting the investigation of whole-body intertissue transport (e.g., vascular permeability and lymphatic drainage). The given examples will demonstrate the utility of computational models in aiding both basic science and clinical research on VEGF systems biology.
Wu
Florence T H
FTH
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Stefanini
Marianne O
MO
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Gabhann
Feilim Mac
FM
Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Popel
Aleksander S
AS
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D003198:Computer Simulation; D005109:Extracellular Matrix / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D008433:Mathematics; D008953:Models, Anatomic; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018919:Neovascularization, Physiologic; D039942:Neuropilin-1 / Q000378:metabolism; D010101:Oxygen Consumption; D016062:Porosity; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020033:Protein Isoforms; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D040262:Receptors, Vascular Endothelial Growth Factor