Functions and therapeutic potential of vascular Orai/CRAC channels

Huge networks of blood vessels (vasculatures) in humans, as well as many other species, enable provision of nutrients to organs and removal of waste; much as transport systems do for cities. The blood vessels have inbuilt capacity to change (remodel) to meet altered demands or adjust in response to injury, which are important for normal physiology and survival in adverse conditions. In disease, the remodelling may be an advantage or disadvantage. In the case of cancer, tumours need to develop their own new blood vessels in order to progress beyond a small size. Therefore, a popular anti-cancer strategy is to try to cut off the tumour?s supply lines, reducing the tumour?s impact or destroying it. Therefore, knowledge of how to manipulate vascular remodelling may be used to enhance the quality of life and survival of people. We propose a project to investigate a promising approach for manipulating vascular remodelling and the perfusion capability of blood vessels, working as a partnership between an academic research group and industrial drug development group to increase efficiency and likelihood of societal benefit.

We have obtained data suggesting importance and therapeutic potential of the recently-discovered Orai proteins and associated CRAC channels in angiogenesis, vascular remodelling and endothelium-dependent relaxation. We have also identified a chemical blocker of the mechanism that has nanomolar potency, strong specificity and approximately 100-fold selectivity for the vascular compared with immune CRAC channel. We propose a project that will test the significance of these findings and the relevance to tumour vasculature and therapeutics. Specific aims of the project include: (i) To generate in vivo conditional disruption of Orai in the mouse to investigate its roles in growth factor-evoked angiogenesis, vascular tone and remodelling in response to injury; (ii) To investigate Orai/CRAC channel function and expression in colonic endothelial cells and endothelial cells from colorectal tumours and associated liver metastases; and (iii) To further explore and develop pharmacological approaches for manipulation of the mechanism, including investigation of chemical blockade, antibody inhibitors and lentiviral delivery of DNA-encoded Orai inhibitor. Through this work we hope to significantly enhance knowledge of Orais in the vasculature and determine whether Orais provide an attractive foundation for developing therapeutic agents that could be used to address problems of colorectal cancer and other important human diseases.