title: Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model.
abstract: Hypoxia is an important physiological stress signal that drives angiogenesis, the formation of new blood vessels. Besides an increase in the production of pro-angiogenic signals such as vascular endothelial growth factor (VEGF), hypoxia also stimulates the production of anti-angiogenic signals. Thrombospondin-1 (TSP-1) is one of the anti-angiogenic factors whose synthesis is driven by hypoxia. Cellular synthesis of TSP-1 is tightly regulated by different intermediate biomolecules including proteins that interact with hypoxia-inducible factors (HIFs), transcription factors that are activated by receptor and intracellular signaling, and microRNAs which are small non-coding RNA molecules that function in post-transcriptional modification of gene expression. Here we present a computational model that describes the mechanistic interactions between intracellular biomolecules and cooperation between signaling pathways that together make up the complex network of TSP-1 regulation both at the transcriptional and post-transcriptional level. Assisted by the model, we conduct in silico experiments to compare the efficacy of different therapeutic strategies designed to modulate TSP-1 synthesis in conditions that simulate tumor and peripheral arterial disease microenvironment. We conclude that TSP-1 production in endothelial cells depends on not only the availability of certain growth factors but also the fine-tuned signaling cascades that are initiated by hypoxia.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Chen
authors.identifier: 0000-0003-1361-8419
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Vascular Medicine Institute, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Isenberg
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Aleksander S
authors.initials: AS
authors.lastname: Popel
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology; D019295:Computational Biology; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D019700:Thrombospondin 1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors
chemical_list: D051785:Smad Proteins; D019700:Thrombospondin 1; D014157:Transcription Factors; D010100:Oxygen