Sarah Childs

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.

Project in vascular patterning:

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.

Project in vascular stabilization:

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 mural cell 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.

Project in microRNA control of smooth muscle differentiation:

MicroRNAs are small RNAs that exert control by binding to mRNAs and blocking translation. We have demonstrated the role of several microRNAs on smooth muscle maturation. In this project, we are exploring how single microRNAs control multiple target genes to control development. We are also exploring how multiple microRNAs impinge on the same target mRNA to finely tune its expression.

Precision medicine using the zebrafish:

A number of rare genetic disorders are due to mutations in novel genes. We use the zebrafish to determine whether mutations in some of these unknown novel genes causes disease by making zebrafish knockout models using CRISPR mutagenesis and examining their phenotype. We can also use these models to develop possible therapeutic strategies. We are supported by the CIRH Rare Diseases Models and Mechanisms Network for this work.

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.