Sarah Childs lab

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 and stem cell 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 stable 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? How do they aquire the mural cell support cells that prevent them from degrading or bleeding? In this project we look at the specification and differentation of vascular mural cells. We discovered that NKX3.1 is expressed and required in mural cell progenitors for controlling their numbers and differentiation.

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 model 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 vascular development genes we study are vascular anomoly genes, Rasa1, GNAQ, and vascular stabilization genes FOXC1 and FOXF2.

Vascular stabilization:

The origins of mural cells are not well understood. In the head, mural cells are thought to originate in neural crest and mesoderm 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 mural cell development. Using transgenic smooth muscle and pericyte marker lines combined with genetic mutants 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. Several of the mutants have mutations in genes that also lead to human stroke, allowing us to mechanistically model changes to the vasculature.

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.

Stem cell models of human genetic cerebrovascular disease:

Common genomic variants point to genes associated with stroke and Cerebral Small Vessel Disease. In this project we use a combination of zebrafish genetics for an whole animal understanding of vascular development and disease-associated changes across the lifespan, and stem cell biology to understand human-specific effects of expression changes in these genes. We differentiate vascular lineages to specifically understand the transcriptional, cellular, morphological and biochemical changes that occur with CSVD-associated mutations.