We study the growth and interactions of cells in their natural environment – the animal – and how these interactions are modified in disease. We focus on the mechanisms that control the process of blood vessel formation, which is crucial to successful development and required in cancer and other diseases. There are currently several areas of investigation that utilize genetically altered mice and cells derived from those mice.
1) We developed a cell culture model of developmental blood vessel formation to study cross-talk between cellular processes such as cell division and sprouting migration to expand vessel networks. Mouse embryonic stem cells are induced to differentiate in dishes to form structures that contain some embryonic tissues, including primitive blood vessels. We have incorporated GFP reporter genes to visualize the dynamic processes of blood vessel formation via time-lapse imaging, and we have used both genetic manipulation and inhibitors to dissect the role of an important signaling pathway (VEGF) in these processes.
2) We study the role of a novel gene that activates cellular homologs of oncogenes (ie Ras) in the proper function of blood vessels. We showed that while this gene is not required for development, it is required for the response of vessels to phorbol esters, which are tumor promoters. This suggests that the signaling pathway using this gene is important in diseases such as diabetes and cancer, and we are testing these models.
3) We investigate how blood vessels know where to go as they form, by using chimeric embryos that consist of a host bird embryo with inserted mouse tissue. This technique allows us to determine the migration patterns of blood vessels over time during fetal development, and we can genetically manipulate the mouse tissue. We can also introduce exogenous DNA into the host via electroporation of the embryos. This analysis has thus far uncovered a crucial role for VEGF in the patterning of vessels around the neural tube, which will form the brain and spinal cord.