Systems Biology Laboratory
Multiscale modeling has emerged in recent years as a powerful methodology to integrate the different levels of biological organization spanning multiple spatial and temporal scales. We are applying the methods of multiscale modeling to problems of cancer and cardiovascular disease.
Systems Biology of Angiogenesis
Angiogenesis (the growth of new blood vessels) is critical in such diverse areas as cancer, cardiovascular disease, age-related macular degeneration, arthritis, diabetes, wound healing, and tissue engineering. We are interested in achieving a quantitative understanding of the mechanisms of microvascular network formation and learning how to control angiogenesis for therapeutic purposes. Using combinations of computational modeling, bioinformatics, and in vitro and in vivo experimentation (systems biology approaches) we analyze the signaling pathways leading to angiogenesis, and the cellular mechanisms governing capillary sprouting and vascular network formation. We have investigated such major molecular players as Vascular Endothelial Growth Factors (VEGF) and their interactions with endothelial cell receptors, Matrix Metalloproteinases (MMPs) and their role in the extracellular matrix proteolysis and release of growth factors, and a transcription factor Hypoxia Inducible Factor HIF-1alpha. We are constructing multiscale models of angiogenesis spanning several levels of biological organization. We use bioinformatics for discovery of novel agents that affect angiogenesis and perform in vitro and in vivo experiments to test these predictions.
Systems Biology of Breast Cancer
Breast cancer is the most commonly diagnosed female malignancy in the United States. Cancer metastasis is a complex process involving dissemination of cancer cells from the primary tumor to distant organs via blood and lymphatic vessels and subsequent colonization of these organs. Metastasis is the major cause of cancer mortality, thus it is very important to understand the mechanisms of tumor growth and metastasis and find ways to inhibit these processes. We study these problems using coordinated computational and experimental approaches.
Systems Biology of Peripheral Artery Disease
Peripheral artery disease (PAD) is a manifestation of atherosclerosis that causes impaired blood flow to the extremities. Peripheral artery disease affects 12 to 15 million people in U.S. and its prevalence is comparable to that of coronary artery disease. Therapeutic angiogenesis is a strategy that promotes blood vessel growth to improve tissue perfusion. We use bioinformatics, computational modeling, and in vitro and in vivo experimentation to solve problems in PAD. Using bioinformatics approaches, we study protein networks that determine processes of angiogenesis, arteriogenesis and inflammation in PAD. We also investigate drug repurposing for potential applications as stimulators of therapeutic angiogenesis. Using computational modeling approaches, we investigate signal transduction pathways and build 3D models of angiogenesis using differential equations-based and agent-based approaches. This research is performed in collaboration with Dr. Brian H. Annex, Director of Cardiology at the University of Virginia.
Discovery of Anti-Angiogenic and Anti-Lymphangiogenic Therapeutic Peptides
Using bioinformatics methods, our laboratory discovered over a hundred of novel anti-angiogenic peptides. We then embarked on experimental in vitro and in vivo studies testing their activity under different conditions. We investigated structure-activity relationship (SAR) doing point mutations and amino acid substitutions and constructed biomimetic peptides derived from their endogenous progenitors. Some of the peptides exhibit anti-lymphangiogenic properties, in addition to anti-angiogenic. We have demonstrated efficacy of selected peptides in mouse models of breast, lung and brain cancers, and in age-related macular degeneration.
Inhibition of angiogenesis (neovascularization) in age-related macular degeneration
We apply anti-angiogenic peptides as therapeutic agents in several animal models of age-related macular degeneration. This research is carried out in collaboration with Dr. Peter A. Campochiaro, Professor of Ophthalmology. We are also collaborating with Dr. Jordan J. Green of Biomedical Engineering who is developing sustained delivery vehicles using nanotechnology for long-term delivery of the peptides.