个人简介

B.Sc. (Bachelor of Science) Ph.D. (Doctor of Philosophy)

研究领域

Molecular and Development Genetics

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 role in disease 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. 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 are been found to be important for zebrafish vascular development have been found to be important for human or mouse vascular development as well. 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.

近期论文

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Tamplin, O.J., Durand, E.M., Carr, L.A., Childs, S.J., Hagedorn, E.J., Li, P., Yzaguirre, A.D., Speck, N.A. & Zon, L.I. Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche. Cell 160, 241-252 (2015). Goi, M. & Childs, S.J. Patterning mechanisms of the sub-intestinal venous plexus in zebrafish. Dev Biol (2015). Arnold, C.R., Lamont, R.E., Walker, J.T., Spice, P.J., Chan, C.K., Ho, C.Y. & Childs, S.J. Comparative analysis of genes regulated by Dzip1/iguana and hedgehog in zebrafish. Dev Dyn 244, 211-223 (2015). Whitesell, T.R., Kennedy, R.M., Carter, A.D., Rollins, E.L., Georgijevic, S., Santoro, M.M. & Childs, S.J. An alpha-Smooth Muscle Actin (acta2/alphasma) Zebrafish Transgenic Line Marking Vascular Mural Cells and Visceral Smooth Muscle Cells. PloS one 9, e90590 (2014). Sarsons, C.D., Yaehne, K., Tekrony, A., Childs, S.J., Rinker, K.D. & Cramb, D. Testing nanoparticles for angiogenesis-related disease: Charting the fastest route to the clinic. Journal of Biomedical Nanotechnology 10, 1641-1676 (2014). French, C.R., Seshadri, S., Destefano, A.L., Fornage, M., Arnold, C.R., Gage, P.J., Skarie, J.M., Dobyns, W.B., Millen, K.J., Liu, T., Dietz, W., Kume, T., Hofker, M., Emery, D.J., Childs, S.J., Waskiewicz, A.J. & Lehmann, O.J. Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease. The Journal of clinical investigation 124, 4877-4881 (2014). Ebert, A.M., Childs, S.J., Hehr, C.L., Cechmanek, P.B. & McFarlane, S. Sema6a and Plxna2 mediate spatially regulated repulsion within the developing eye to promote eye vesicle cohesion. Development 141, 2473-2482 (2014). Yaehne, K., Tekrony, A., Clancy, A., Gregoriou, Y., Walker, J., Dean, K., Nguyen, T., Doiron, A., Rinker, K., Jiang, X.Y., Childs, S. & Cramb, D. Nanoparticle accumulation in angiogenic tissues: towards predictable pharmacokinetics. Small 9, 3118-3127 (2013). Zeng, L. & Childs, S.J. The smooth muscle microRNA miR-145 regulates gut epithelial development via a paracrine mechanism. Dev Biol 367, 178-186 (2012). Liu, J., Zeng, L., Kennedy, R.M., Gruenig, N.M. & Childs, S.J. betaPix plays a dual role in cerebral vascular stability and angiogenesis, and interacts with integrin alpha(v)beta(8). Developmental Biology 363, 95-105 (2012). Ebert, A.M., Lamont, R.E., Childs, S.J. & McFarlane, S. Neuronal expression of class 6 semaphorins in zebrafish. Gene Expr Patterns 12, 6 (2012). Lamont, R.E., Vu, W., Carter, A.D., Serluca, F.C., MacRae, C.A. & Childs, S.J. Hedgehog signaling via angiopoietin1 is required for developmental vascular stability. Mech Dev 127, 159-168 (2010). Christie, T.L., Carter, A., Rollins, E.L. & Childs, S.J. Syk and Zap-70 function redundantly to promote angioblast migration. Dev Biol 340, 22-29 (2010). Zeng, L., Carter, A.D. & Childs, S.J. miR-145 directs intestinal maturation in zebrafish. Proc Natl Acad Sci U S A 106, 17793-17798 (2009). Liu, J., Fraser, S.D., Faloon, P.W., Rollins, E.L., Vom Berg, J., Starovic-Subota, O., Laliberte, A.L., Chen, J.N., Serluca, F.C. & Childs, S.J. A bPix-Pak2a signaling pathway regulates cerebral vascular stability in zebrafish. Proc Natl Acad Sci U S A 104, 13990-13995 (2007).