Endothelial cell growth and signalling in the mouse
The receptor tyrosine kinase (RTK) family of cell surface proteins is known to play key roles in cell-cell communication in multi-cellular metazoan organisms. Genetic and biochemical studies on this large family of proteins have shown that different RTKs are responsible for transducing important developmental, proliferative, cell survival and migratory signals from the outside to the inside of the cell. The development and proper functioning of cell systems as diverse as the compound eye in the fly, the vulva in the nematode and hematopoiesis and endothelial growth in the mouse all depend on intact signalling pathways that are controlled by different members of the RTK family.
Our lab is investigating the signal transduction pathways of different RTKs during vascular development in the mouse and during tumour formation. Vascular endothelial cells constitute an unusually quiescent epithelial cell population. The turnover rate of both large and small vessel endothelium is very low. The mechanisms that underlie this growth control are not well understood and the factors that initiate and control subsequent proliferation are unknown. It is clear, however, that vascular growth occurs under nonpathological conditions (e.g., wound healing, corpus luteum formation and development) and that this growth is somehow terminated at the correct time. In contrast, uncontrolled vessel growth (including tumour vascularization, diabetic retinopathy and arthritis) is associated with many different diseased states. The determinants that control these processes remain unknown; however the study of peptide growth factors, their receptors and their downstream substrates will provide both a biochemical and genetic entry point into the elucidation of the underlying controls of these processes.
To address the importance of these different RTKs and their related signal transduction pathways during vascular growth in development and in disease, we use:
- gene-targeting in embryonic stem cells
- transgenic mice
- receptor biochemistry