Sarah Childs

Developmental angiogenesis and vascular stabilization using the zebrafish model. Modelling of human vascular disease. Pericyte and vascular smooth muscle specification and differentiation.

We are interested in angiogenesis, the process by which new blood vessels develop. Blood vessels first develop as naked endothelial tubes, and then acquire a coating of ‘mural’ cells (either smooth muscle cells or pericytes). Dysfunctional vessels underlie a large number of serious diseases. We focus on using developmental biology to tease out the signals that grow and stabilize new blood vessels as a means to potential therapy for blood vessel disorders.

How do blood vessels develop a vascular tree?

Blood vessels are customized for delivery of oxygen and nutrients to different organs with different architectures and metabolic needs. How do blood vessels acquire organ-specific patterns? In this project we examine the normal patterning of blood vessels during development and the molecular pathways that control their pattern. We also examine the role of patterning genes such as the PlexinD1 receptor to determine how it guides vascular development using genetic analysis of ligands and signalling pathways. We have a strong interest in GTPase control of the actin cytoskeleton in vascular development, and their particular roles in diseases such as vascular malformation.

Using the zebrafish to understand rare genetic disease:

Advances in genomics has resulted in mutations being identified in genes of unknown function that may lead to disease. But if the gene is unknown, how do we know what it does and whether it could be causing the disease. In my laboratory, we create mutations similar to patient mutations in genes where the function is incompletely understood. We can then study the effects of these mutations at the organismal level and see how they lead to changed development or blood vessel growth/fuction. Examples of genes we study are vascular anomoly genes, Rasa1, GNAQ, vascular stabilization genes FOXC1, FOXF2, heart development gene ILK1.

Vascular stabilization, smooth muscle and pericyte differentiation:

The origins of mural cells are not well understood. In the head, mural cells are thought to originate in neural crest cells, but how do they migrate to specific vessels and what signals allow them to contact and ensheath endothelial cells? In this project we examine the genetic control of pericyte and vascular smooth muscle development. Using transgenic smooth muscle and pericyte marker lines we trace mural cell migration in real time. Loss of mural cell attachment to endothelial cells results in brain hemorrhage. We have developed mutant animals with defective vascular stabilization that are models of both hemorrhagic and ischemic stroke.

The zebrafish model:

We use zebrafish as a model system because as a vertebrate, their cardiovascular system is very similar to that of mammals. Furthermore, there is close similarity from a genetic point of view. To date, genes that have been found to be important for zebrafish vascular development have also been found to be important for human or mouse vascular development. Zebrafish are a common tropical fish which develop as transparent, externally fertilized embryos. We can observe their development during all stages of embryogenesis under a microscope. This allows us to do very detailed screens for subtle genetic defects, and is in contrast to mammals which develop in utero and are inaccessible. The capacity for live confocal imaging of development using this model is outstanding.

Research Areas:

Molecular and Development Genetics

Research Personnel:

• Dr. Jae-Ryeon Ryu, Research Associate
• Dr. Suchit Ahuja, Research Associate
• Danielle Blackwell, Technician
• Dr. Sean McGarry, Postdoctoral Associate 
• Jasper Greysson-Wong, PhD Graduate Student
• Ruchita Shandilya, PhD Graduate Student
• Cynthia Adjekukor, MSc Graduate Student
• Emma Heeg, MSc Graduate Student
• Merry Faye Graff, MSc Graduate Student
• Leslie McGill, Administrative Assistant