Elucidating the extracellular role of FKBPL as a regulator of angiogenesis

Angiogenesis, the growth of new capillary blood vessels, is an important physiological process essential for healing and reproduction. The body controls angiogenesis by maintaining a precise balance of growth and inhibitory factors in healthy tissues. When this balance is disturbed, a wide range of diseases can arise including cancer, psoriasis, age-related blindness, diabetic ulcers, cardiovascular disease, stroke, and many others. The list of diseases that have angiogenesis as an underlying mechanism grows longer every year. It is therefore important that the factors that control the angiogenic process are well understood. When angiogenic growth factors are produced in excess of angiogenesis inhibitors, the balance is tipped in favour of blood vessel growth. When inhibitors are present in excess of stimulators, angiogenesis is stopped. The normal, healthy body maintains a perfect balance of angiogenesis modulators. We have identified a novel protein, called FKBPL, that occurs naturally in the body, and has potent anti-angiogenic activity. We know this because when we add FKBPL to growing tumours it prevents their growth by stopping angiogenesis within the tumour, starving it of oxygen and nutrients. We now need to understand the precise actions of this protein in the body during blood vessel development, allowing us to understand its role in the diseases outlined above. We will therefore study the normal role of FKBPL during blood vessel development in two angiogenesis models. We will do this using a molecular technique to prevent expression of this protein and then assess the effects on blood vessel development. This will tell us how critical FKBPL is in controlling this process. We also aim to study how FKBPL is switched on and off to control blood vessel development. This is also important since if the protein is not properly regulated it will cause an imbalance in angiogenesis which may lead to disease. We also aim to understand what happens within the endothelial cells, the cells that form the inner lining of all blood vessels. We know that too much of the protein stops the cells from moving so that they cannot form new blood vessels, but we need to know how the cells signal to regulate this process. Increasing and decreasing the levels of FKBPL in endothelial cells and looking at the signalling events that take place will be important. In summary, we believe that a more detailed investigation of the role of the FKBPL protein in the normal processes involved in angiogenesis will help our understanding of a wide range of diseases that are associated with disrupted or imbalanced angiogenesis. This could have a profound effect on how we develop new treatments for a wide range of common diseases.

Angiogenesis is a tightly regulated process with key physiological roles in the body. Errors in its regulation are implicated in a wide range of pathologies. A detailed understanding of the underlying mechanisms will have a significant impact on human health, mainly in the aging population. We have identified a novel, naturally secreted protein, FKBPL, that has potent anti-angiogenic activity and demonstrated that it prevents endothelial cell migration, leading to potent inhibition of angiogenesis in growing tumours. Its activity appears to be dependent on CD44, which is distinct from the well-characterised VEGF/VEGFR-associated pathways, making it attractive in terms of drug development. However, we know very little about the normal role of FKBPL during developmental angiogenesis or under what stimulus this protein is activated/secreted to inhibit this process. The aim of this project is therefore to fully characterise the physiology of FKBPL during developmental/physiological angiogenesis using loss of function approaches and to elucidate the signalling mechanisms leading to FKBPL activation/secretion. We will characterise angiogenesis in FKBPL knockout mice or following delivery of an FKBPL inhibitory antibody or potent anti-angiogenic FKBPL-derived peptide for comparison. We will also use the well-established zebrafish model, of developmental angiogenesis. Phenotypic changes will be examined following FKBPL knock-down with targeted morpholinos or following treatment with the FKBPL peptide; the dependency on FKBPL's target, CD44 will also be assessed. Finally, at a more basic cellular level we will identify the molecular signals leading to FKBPL's secretion/extracellular activation and downstream signalling. In summary, this study will identify the role played by FKBPL during the angiogenesis, ultimately facilitating our understanding of this process in human disease.

Angiogenesis is one of the main research focuses among the pharmaceutical giants. This is because angiogenesis is a key process that occurs during both physiological and pathological disease processes. It is associated with more than 70 major health conditions affecting children and in particular aging adults, in developed and developing nations. We have identified a new, anti-angiogenic protein, FKBPL, and now aim to investigate its endogenous role. The wide ranging impact this protein may have on the patients suffering from conditions associated with angiogenesis will be realised only once its physiological activities are fully characterised. In this respect, we have already generated a therapeutic peptide that is undergoing clinical development in the oncology field in collaboration with Almac Discovery. If we can demonstrate that FKBPL has a wider role within the developing vasculature, as proposed within the present study, we could expand the potential applications of our therapeutic peptide or indeed develop knock-down approaches to enhance angiogenesis in diseases where this would be appropriate such as cardiovascular disease and stroke. We will therefore ensure that new intellectual property developed within the current project is properly protected so that continued interest from pharma is maintained. We have extensive experience in this respect, having already demonstrated that we can translate basic research into meaningful clinical applications. We would then aim to publish in high impact journals with a wide readership and will ensure that any exciting data are publicised by the media. We will also ensure that the models we generate within this study are made freely available to other scientists to expand further their knowledge of the angiogenesis field. Economically our research could have huge impact, with our drug being developed by British pharma to target diseases affecting the worldwide population. Here we could have a major impact on health and well-being in the UK and worldwide.