Systems Biology Laboratory


Systems Biology of Cancer

The overarching goal of the Systems Biology Laboratory is to apply modern methods of biomedical engineering to better understand the mechanisms of cancer and to significantly advance treatments for this devastating disease. Cancer cells invade into healthy tissues and co-opt these tissues into promoting tumor growth and metastasis. They use multitude of ways to evade therapeutics by adapting to drugs making them ineffective. To control and conquer the disease, the applications of modern quantitative methods are absolutely necessary; our laboratory is at the cutting edge of the cancer systems biology research. The research in the laboratory is broad and uses a combination of experimental and computational approaches. We investigate cancer at different levels from genes to proteins to tumor, and eventually to the whole body. We look into the ways the factors that stimulate tumor growth (eg growth factors) signal to the interior of the cell, and how cancer cells communicate with their neighbors such as immune cells and vascular cells. We develop and test novel drugs to treat different types of cancer. Our research focuses on the following areas:

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.

Multiscale Modeling

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.

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.