PI3K/ ANGIOGENESIS · The role of p110beta isoform of PI 3-kinase in endothelial cells and angiogenesis
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2007-01-01 → 2008-12-31
- EU contribution
- €167,664
- Participants
- 2
- Scheme
- EIF
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Results in brief
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.
Data: CORDIS, © European Union
Project objective
PI 3-kinases (PI3Ks) are key signal transduction enzymes which are generally considered to be excellent new targets for therapeutic interference. Mammals have multiple PI3K isoforms. Here, I seek to investigate the role of the p110beta PI3K isoform in endothelial cells and angiogenesis, the growth of new blood vessels.The functions and activities of endothelial cells depend on input from growth factors, chemokines and adhesion molecules. All of these agents are known to signal through PI3K. Indeed, there i s evidence for a role for PI3K activity in angiogenesis, but the roles of the distinct PI3K isoforms in this phenomenon are unknown.Thus, I propose to investigate the role of the p110beta PI3K isoform in angiogenesis. I will use new PI3K mutant mice with a constitutively or conditionally inactive p110beta, which the Host Group has created (unpublished), and derived endothelial cells. At present, the physiological role of p110beta is completely unknown, and this PI3K isoform is one of the most enigmatic to d ate.The Host Group has found that p110beta expression is highly enriched in endothelial cells, providing a strong indication of its role in this cell type. Other than work in vivo, the proposed work will also cover detailed mechanistic investigations at t he cellular level in isolated endothelial cells, complemented by the use of isoform-selective PI3K inhibitors developed with Host Group collaborations.This post-doctoral period will allow me to be familiarized with advanced and unique approaches used by t he Host Group, including gene-targeted mice and sophisticated cell biology.Other than widening my scientific horizon and allowing me to establish international contacts, this project will also widen my expertise in basic research to the field of angiogenesis in which I have developed a great interest.It is my ultimate aim to continue my career the findings obtained from the proposed project by securing a future independent research position in France.
Original text from CORDIS.
Participants
- QUEEN MARY & WESTFIELD COLLEGE, UNIVERSITY OF LONDON · LONDONCoordinatorCity levelUnited Kingdom
- LUDWIG INSTITUTE FOR CANCER RESEARCH · LONDONUnited Kingdom
Links
Data: CORDIS, © European Union