Title: Understanding CD148: A disease 'off switch'
Funder: Dunhill Medical Trust

Abstract: Cellular processes involved in tissue repair are driven by a complex network of signalling pathways. Central to this is the phosphorylation of proteins by tyrosine kinases and dysregulation of these processes leads to adverse pathological effects. Protein phosphorylation is generally associated with the activation of signalling pathways, however, there are also a smaller family of proteins, the tyrosine phosphatases which act to dephosphorylate kinases and other important molecules. One such example is the protein tyrosine phosphatase receptor CD148 (Dep 1, PTPRJ). Our group was the first to identify a ligand for this receptor, the shed form of the proteoglycan syndecan-2, and have since demonstrated that syndecan-2 derived peptides can inhibit new blood vessel formation (angiogenesis) in a number of model systems via engagement with CD148 [1, 2]. Importantly, we can show that these peptides are effective in non-clinical models of wet age related macular degeneration (Wet AMD) and diabetic retinopathy and represents an alternative to anti-VEGF therapies currently in use. Independently, our collaborator’s team (Ivan Rosas) have recapitulated our findings and discovered that engagement of CD148 by a syndecan-2 derived peptide leads to an inhibition of fibrosis both in vitro, and in an in vivo model of idiopathic pulmonary lung fibrosis [3]. This compelling preliminary data suggests that CD148 is an important therapeutic target for both neovascular eye diseases and any number of fibrotic diseases. Despite the progress made by both groups, there is still much to learn about the biology of CD148. Both applicants have demonstrated that upon activation it acts to dephosphorylate the p85 subunit of PI3 kinase and as a result down regulate downstream PI3K dependent signalling pathways [1, 3]. In endothelial cells (ECs), this results in impaired cell migration responses (an essential component of angiogenesis) and in lung fibroblasts reduced matrix deposition, cell migration, and reduced transition to a myofibroblastic phenotype (all critical to fibrotic disease). The collective work of both groups has highlighted the significant potential of targeting CD148 in disease. The aim of this project is to build on this exciting preliminary data (from both groups) and to gain further insight into CD148 biology with a view to deriving further novel therapeutics for the treatment of both neovascular and fibrotic disease (both common in aging individuals).

Lay abstract: Cells in the human body respond to each other, and molecules around them, by the action of molecules on their surface called receptors. Cells have many different types of receptors and each one recognises different molecules (ligands). The consequence of a receptor engaging with its ligand is the receptor generates a signal inside the cell which can alter the cells behaviour. In a healthy human, these interactions help in our growth and development, in the way we fight infection and the way in which we heal ourselves. In some diseases, these processes become disturbed and cells respond in a way that is deleterious to health. One such example is Wet Age Related Macular degeneration in which new blood vessels grow at the back of a patient’s eye causing loss of vision. The reasons for why this happens are not known but there are medicines which can be used to slow or stop the new blood vessels forming. We have discovered one such medicine, QM107, which is a molecule that interacts with a receptor called CD148. We believe that when QM107 engages with CD148, it sends a signal inside the cell which turns off many of the processes that are associated with this disease. We can also show that CD148 acts in a similar way in a lung disease called idiopathic pulmonary lung fibrosis. For these reasons, we think that understanding more about how CD148 works will enable us to make more medicines which can exploit this receptor ‘off switch’. In this project, we will find out ways to control this receptor to improve outcomes in eye diseases, and based on this information derive a new drug which may improve or replace existing therapies for wet age related macular degeneration and possibly fibrotic disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: EYE