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People

Prof. Ian Zachary

Research Lead

Professor Ian Zachary

Contact us

Centre for Cardiovascular Biology and Medicine

BHF Laboratories, Rayne Building
5 University Street
London WC1E 6JJ

Tel: +44 (0)20 7679 6339

Vascular signalling

Vascular Signalling - A live Casper:Fli-eGFP Zebrafish at the juvenile stage (30 days) showing the vasculature (green) and internal organs (pseudocoloured red). Casper fish (named after Casper the friendly ghost) are genetically unpigmented and Fli-eGFP fish express eGFP (green fluorescent protein) specifically in the vasculature. We developed the Casper:Fli-eGFP Zebrafish in our laboratory to combine these two properties, enabling us to perform imaging of the blood vessels in juvenile and adult fish more easily. The image shows the result of volumetric imaging using optical tomography.

Overview

Our research investigates the mechanisms underlying regulation of blood vessel formation and function of the mature cardiovascular system by Vascular Endothelial Growth Factor (VEGF) and other growth factors. A major focus of this work is to identify the signalling pathways and receptors involved in these biological functions of VEGF, communication between them and how they integrate into physiologically relevant networks. We are pursuing these aims through in vivo analysis in disease and genetic models, combined with imaging and biochemical studies in cell culture. Another important aspect of our work is the development of new therapeutic approaches designed either to promote or to inhibit VEGF functions dependent on the disease context. Research in our centre is supported by major programme grant funding from the British Heart Foundation, and additional funding from the European Commission (EC), and Biotechnology and Biological Sciences Research Council (BBSRC).

Key research activities

Role of Neuropilins in Angiogenesis and VEGF Signalling

Neuropilins (NRP) are co-receptors for VEGF with an essential role in angiogenesis in development. Our recent work has highlighted selective roles for NRP1 both in VEGF signalling and in cell migration and our aim is to investigate the mechanisms involved in these key processes and the important molecular partners for NRP1 in angiogenesis using novel in vivo models and diverse experimental analysis of cell cultures. 

Developing Neuropilin-Targeted Therapies

NRPs have emerged as novel targets for the development of new therapeutic approaches to inhibiting angiogenesis involved in diverse human diseases, including cancer and eye disease. Together with a small biotechnology company called Ark Therapeutics, we are developing novel small molecules designed to inhibit the function of NRP1 in the vasculature, which have therapeutic potential as novel anti-angiogenic drugs. To generate new opportunities for developing therapies targeted at the VEGF/NRP1 signalling axis, we are also investigating the structure of Neuropilins complexed with VEGF in collaboration with investigators in the UCL Department of Structural and Molecular Biology. 

Neuropilin in Regenerative Cardiovascular Medicine

As part of a European Commission-funded consortium, we are exploring the possibility of using Neuropilin gene delivery to enhance the promotion of stem cell-mediated endothelial regeneration after placement of a new biodegradable and magnetisable stent which attracts stem cells labelled with iron nanoparticles. This approach is designed to reduce the problem of “restenosis”, whereby a blockage of the coronary artery in the heart recurs following stent implantation. Role of the Protein Kinase D Pathway in Endothelial Cell Function and Angiogenesis Protein kinase D (PKD) is an important signalling pathway, which our recent work has identified as playing a central role in VEGF signalling in the endothelium. This work is investigating the role of PKD in the endothelium in vivo through the generation of novel model systems, and the use of DNA constructs designed to alter the function of PKD.