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The role of p110beta isoform of PI 3-kinase in endothelial cells and angiogenesis

Final Activity Report Summary - PI3K/ angiogenesis (The role of p110beta isoform of PI 3-kinase in endothelial cells and angiogenesis)

In this proposal we investigated the physiological role of a family of proteins, called PI3Ks. These proteins or isoforms of PI3Ks were involved in transducing messages inside cells and we studied the way in which these proteins, which all induced the same chemical reaction, had distinct roles inside the body. This was of clinical interest since inhibitors of PI3Ks were currently developed and used by pharmaceutical industry in clinical trials for different therapeutic applications, concerning solid and hematologic tumours, inflammation and allergy. These inhibitors could inhibit either one or several proteins of the PI3K family. Knowing the role of each protein of the family was crucial to help design drugs which were specific and prevented off-target effects and discover new applications.

The objective of the proposal was to study the role of one isoform of PI3K, called p110beta, in angiogenesis. Angiogenesis is the formation of new vessels, which occurs during embryonic development but is also involved in the aetiology of different diseases such as cancer. Vessels are formed by endothelial cells.

We created a new and unique genetically modified mouse, which allowed specific inactivating of p110beta in the cells we wanted to study as well as in the entire organism. Extensive characterisation of the mouse lines was performed. P110beta was inactivated in the endothelial cells of the mouse. This inactivation did not alter the proper embryonic development of the mouse, while we unravelled the crucial role of another isoform of PI3K, p110alpha, in this process. Studying the signal transduction downstream of angiogenic signals, such as vascular endothelial growth factor (VEGF) input signal, allowed us to understand why one isoform and not the other was important in embryonic angiogenesis. These results were published as two articles in high standard quality peer-reviewed journals, namely ‘Nature’ and ‘PNAS’.