We are interested in determining functions of novel molecules regulating angiogenesis including receptors, microRNAs and secreted molecules. Typically, we use loss-of-function approaches through knockout and conditional knockout mice. We also have extensive experience using adenoviral expression of soluble receptor ectodomains to inhibit angiogenic pathways including VEGF and PDGFRb. Loss-of-function phenotypes would simulate the effects of pharmacologic inhibition of novel targets for anti-angiogenic therapy of cancer and ocular disorders.
Endothelial cell regulation of physiology
How do endothelial cells regulate physiology of their host organs? The liver hepatocyte appears particularly responsive to its host endothelial cells. We are investigating effects of VEGF inhibition on hepatocyte functions in terms of Epo synthesis, erythropoiesis and metabolic pathways. We are also correlating these changes with anti-tumor response and survival in cancer patients receiving VEGF inhibitors, as potential surrogate biomarkers of efficacy.
Intestinal stem/progenitor biology
The complete regeneration of the epithelial lining of the intestine every 5-7 days renders the intestine a model system for studying stem cell behaviors. We are investigating the regulation of the intestinal stem cell (ISC) compartment by extracellular signals such as Wnts, using adenoviral and conditional knockout approaches. Further, we have derived robust methods for prolonged culture of and ex vivo expansion of primary intestinal tissue, with preservation of ISCs. Additional methods are under development for purification and analysis of mouse and human ISCs.
Nanoparticle-mediated systemic siRNA delivery
The potential of siRNA to silence currently undruggable targets such as intracellular transcription factors is tempered by substantial obstacles to systemic siRNA delivery. We are working collaboratively to use nanoparticle-based methods to target siRNA to cancer cells towards the development of novel cancer therapeutics.