THE ZONAB PATHWAY IN ENDOTHELIAL HOMEOSTASIS AND ANGIOGENIC BEHAVIOUR

The blood delivers nutrients to the different organs of our body. The blood circulates through vessels that are lined by specialised cells called endothelial cells. These cells have a key role in maintaining the health of blood vessels. Endothelial cell function is affected in many different diseases such as diabetes, thrombosis, inflammation, atherosclerosis and cancer. Here, we propose to study the mechanisms that control endothelial cell-cell adhesion, proliferation and migration known to be dysfunctional or aberrantly activated during such pathological conditions. To understand how these different endothelial cell functions are regulated is fundamental to develop new therapeutic strategies to prevent or inhibit such conditions.

Endothelial cell dysfunctions and angiogenic processes contribute to several severe diseases. The control of endothelial gene expression is crucial to maintain homeostasis and regulate angiogenesis. Genes involved in cell adhesion and proliferation play key roles in these processes. ZONAB is a transcription factor involved in cell proliferation whose activity is regulated by the tight junction protein ZO-1. Tight junctions regulate paracellular permeability, gene expression and cell proliferation. Preliminary data generated for this proposal show that ZONAB regulates in vitro angiogenic behaviour, as measured by human umbilical vein endothelial cell (HUVEC) tube formation on Matrigel. This project sets out to determine the role of ZONAB and ZO-1 in endothelial homeostasis and angiogenesis, and to identify new target genes and signalling pathways using a combination of functional and cellular assays, as well as a genomic approach. These studies will increase our understanding of the transcriptional pathways involved in endothelial cell physiology and pathology, and provide possibilities for future therapeutic approaches to prevent thrombosis, inflammation and pathological angiogenesis.