The research in my lab centers on the molecules and processes that control development and disease. Our major focus is the study of how blood vessels form and are patterned during development, and how these processes are disturbed or co-opted during diseases such as cancer. The group of scientists working in my lab include graduate students, post-docs, research technicians, and undergraduates.
The process of blood vessel formation is crucial to vertebrate development, because embryos cannot develop without a source of oxygen and nutrients. Thus, blood vessels begin to form very early in development, along with the heart and primitive blood cells. Pictured here is a mouse embryo, halfway through development, with all the
blood vessels visible. Blood vessel formation is also very important in several common diseases– for example, the occlusion of blood vessels that characterize heart disease is likely to cause a fatal heart attack unless new blood vessels can be formed quickly to nourish the affected heart. Conversely, the blood vessels that form to nourish a small tumor can help the tumor grow and eventually metastasize. Therefore, blocking the formation of tumor blood vessels could provide important cancer therapy.
We use multiple approaches to study blood vessel formation during development and disease. To understand the basic differentiation signals, we utilize an in vitro system in which primitive blood vessels form in a tissue culture dish. We use mouse embryonic stem cells that are undifferentiated but can differentiate to provide every cell type of the mouse. When differentiated in cultures, the cells reproducibly differentiate into a subset of cells, including endothelial cells that are the basic building blocks of all blood vessels. These endothelial cells organize into primitive vessels in culture. Thus, we have easy access to important stages of early blood vessel formation that usually occur in the mother’s body. We have obtained several cell lines that have mutations in genes that are important in blood vessel formation because they disrupt a specific signaling pathway. Click here to see how a mutation in the flt receptor (part of the vascular endothelial growth factor pathway) affects the growth of blood vessels. We can now use this system to watch blood vessels develop in real time…check out some of our movies! We also utilize a sprouting assay where endothelial cells coated on beads form primitive vessels in a 3D matrix. This model has less complexity and can be easier to manipulate by over-expression or gene knockdown, and it also provides metrics for quantitative measurement.
A complementary approach is to study the process of blood vessel formation in vivo. We analyze zebrafish embryos that develop outside the mother and thus can be imaged while developing. Zebrafish can also be genetically mutated, and several lines carry reporter genes that light up blood vessels. We also analyze mouse embryos to verify that conclusions formed from the culture model or zebrafish are valid in vivo. We study aspects of vascular pattern formation in vivo with both zebrafish and mice. We can use fish or mice that have mutations in genes that are important in blood vessel formation. Mice are also used to study normal adult blood vessel formation, such as occurs in wound healing, and in diseases such as cancer.