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Contact: Clare Ryan
clare.ryan@ucl.ac.uk
44-020-310-83846
University College London

Protein responsible for 'bad' blood vessel growth discovered

The discovery of a protein that encourages blood vessel growth, and especially 'bad' blood vessels the kind that characterise diseases as diverse as cancer, age-related macular degeneration and rheumatoid arthritis has been reported in the journal Nature.

The team at the UCL Institute of Ophthalmology discovered the new protein, called LRG1, by screening for mouse genes that are over-expressed in abnormal retinal blood vessels in diseased eyes.

In these diseased retinas the LRG1 protein is expressed by blood vessel endothelial cells, which line blood vessel walls. LRG1 is also present in the eyes of patients with proliferative diabetic retinopathy a vascular complication of diabetes that can lead to blindness.

The study shows that, in mouse models, LRG1 promotes the growth of blood vessels in a process known as 'angiogenesis'. Conversely, inhibition of LRG1 in mouse models reduces the harmful blood vessel growth associated with retinal disease.

The authors of the study suggest that blocking LRG1's activity is a promising target for future therapy.

Professor John Greenwood, senior author of the research from the UCL Institute of Ophthalmology said: "We have discovered that a secreted protein, LRG1, promotes new blood vessel growth and its inhibition prevents pathological blood vessel growth in ocular disease.

"Our findings suggest that LRG1 has less of a role in normal blood vessel growth and so may be particularly applicable to 'bad' blood vessel growth. This makes LRG1 an especially attractive target for therapeutic intervention in conditions where vessel growth contributes to disease."

Angiogenesis is an essential biological process that is required for development, reproduction and the repair of damaged tissues. However angiogenesis also plays a major role in many diseases where new vessel growth can be harmful.

For example, in the retina uncontrolled and irregular blood vessel growth in diseases such as age-related macular degeneration and diabetic retinopathy can result in a catastrophic loss of vision. Another example is the growth of cancerous solid tumours, which are dependent on the proliferation of new blood vessels. Angiogenesis is also an important feature of rheumatoid arthritis, where it contributes to the inflammation of the joint.

In previous studies, many signaling molecules have been identified that control angiogenesis, with the secreted protein vascular endothelial growth factor (VEGF) being considered as the master regulator. Therapeutic targeting of VEGF has resulted in improved outcomes in eye diseases with vascular complications and in some cancers but it is clear that additional therapeutic targets need to be identified.

The mechanism through which LRG1 promotes angiogenesis is by modifying the signalling of a multifunctional secreted growth factor called transforming growth factor beta (TGF-beta). TGF-beta regulates both the maintenance of normal healthy blood vessels, and the unwanted growth of harmful blood vessels, but precisely how it promotes two opposing outcomes is a biological paradox.

This study indicates that in the retinal diseases investigated LRG1 production is 'turned on' in blood vessels. This causes a switch in TGF-beta signalling away from a normal vessel maintenance pathway towards a pathway that promotes the growth of new harmful blood vessels.

Professor Stephen Moss, senior author from the UCL Institute of Ophthalmology said: "Genetic studies have revealed that the gene that codes for LRG1 is conserved in vertebrates, and this study confirms that mouse and human blood vessels express LRG1.

"We predict, therefore, that abnormal blood vessel growth is also a conserved process and that the role of LRG1 is equally applicable to human pathological angiogenesis."

He added: "Work is already underway to develop a therapeutic antibody that targets LRG1."

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The research was funded by the Medical Research Council, the Lowy Medical Research Foundation, UCL Business, the Rosetrees Trust, the National Institute for Health Research (NIHR) Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology (who are advising on the translational pathway) and the British Heart Foundation.

Contacts

Professor John Greenwood
UCL Institute of Ophthalmology
Tel: 0207 6086858
Mobile: 07900224435
Email: j.greenwood@ucl.ac.uk

Professor Stephen Moss
UCL Institute of Ophthalmology
Tel: 0207 6086973
Mobile: 07906907471
Email: s.moss@ucl.ac.uk

Clare Ryan
UCL Media Relations
Tel: +44 (0)20 3108 3846
Mobile: +44 07747 556 056
Email: clare.ryan@ucl.ac.uk

Notes for Editors

1. 'LRG1 promotes angiogenesis by modulating endothelial TGF-b signalling' is published today in Nature. For copies of the paper please contact UCL Media Relations.

2. Images from the research are available to journalists from UCL Media Relations

About UCL (University College London)

Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender and the first to provide systematic teaching of law, architecture and medicine.

We are among the world's top universities, as reflected by our performance in a range of international rankings and tables. According to the Thomson Scientific Citation Index, UCL is the second most highly cited European university and the 15th most highly cited in the world.

UCL has nearly 27,000 students from 150 countries and more than 9,000 employees, of whom one third are from outside the UK. The university is based in Bloomsbury in the heart of London, but also has two international campuses UCL Australia and UCL Qatar. Our annual income is more than 800 million.

http://www.ucl.ac.uk | Follow us on Twitter @uclnews | Watch our YouTube channel YouTube.com/UCLTV

UCL Institute of Ophthalmology

UCL Institute of Ophthalmology is one of the foremost eye and vision research institutes in the world. It operates at the cutting-edge of translational research, delivering new therapies, diagnostic tools and preventive measures to patients suffering from visual impairment or blinding conditions. The combination of the Institute's research resource with Moorfields Eye Hospital, which has the largest ophthalmic patient population in the Western World, opens the way for further advances in vision research. The Institute is a recipient of a Queen's Anniversary Prize for Higher and Further Education, in recognition of outstanding research excellence. For further information, please visit http://www.ucl.ac.uk/ioo

About the National Institute for Health Research

The National Institute for Health Research (NIHR) is funded by the Department of Health to improve the health and wealth of the nation through research. Since its establishment in April 2006, the NIHR has transformed research in the NHS. It has increased the volume of applied health research for the benefit of patients and the public, driven faster translation of basic science discoveries into tangible benefits for patients and the economy, and developed and supported the people who conduct and contribute to applied health research. The NIHR plays a key role in the Government's strategy for economic growth, attracting investment by the life-sciences industries through its world-class infrastructure for health research. Together, the NIHR people, programmes, centres of excellence and systems represent the most integrated health research system in the world. For further information, visit the NIHR website (http://www.nihr.ac.uk).

The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

About Rosetrees Trust

Rosetrees Trust is a substantial family foundation established in 1987 that funds life changing medical research. Rosetrees has donated millions of pounds of family money to leading researchers in all the main areas of bio-medical research, including brain and neurological disorders, cancer, cardiovascular disease, imaging, lung damage, nano-technology, regenerative medicine, rheumatology and stroke. Rosetrees currently supports over 200 live medical research projects, with a vision to fund researchers whether established, or young and promising with the potential to become future leaders in their field. Since Rosetrees' establishment over 25 years ago, in excess of 130 million has been invested in world class research, either from Rosetrees, co donations or the major grants that followed from Rosetrees' initial support. Rosetrees has a target of generating 1 billion for medical research.

Rosetrees' unique entrepreneurial philanthropy model sources and selects only the best projects and researchers to support, and then carefully manages the funding throughout the duration. Rosetrees actively seeks trusts and philanthropists to co donate with in order to direct more funds to the best medical research projects, and co donors who fund alongside Rosetrees benefit at no cost from this expertise.



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