For over ten years Dr Mark Dockrell has been interested in identifying the signal pathways inside cells to better understand how the cell works and to possibly identify new targets for medicines.
TGF-beta is a growth factor involved in a number of diseases including kidney fibrosis. It signals between cells and mediates a wide range of events such as; the production of scar tissue by regulating extracellular matrix proteins, cell differentiation and anti-inflammatory responses. The regulation of such a variety of outcomes by a single growth factor implies that the effects of TGF-beta are regulated by complex signalling pathways in the cell. Much of Dr Dockrell's work involves attempting to dissect some of these signalling pathways.
The signalling pathway currently under investigation include the Smad pathway, the Ras/MAP kinase pathway, and the more recently identified Erk5 signalling pathway.
in Proteinuria we believe that Albumin Protein sticks to Megalin on the surface of the cell. Within the cell, messages are then transmitted from Megalin. Recently, Dr Dockrell has been trying to identify what signals are transmitted within the cell from Megalin and how these signals might relate to scarring of the kidney (interstitial fibrosis). Within our laboratories, we are focusing on two candidate signalling pathways; the MAP kinase pathway and the novel and less understood Dab2 signalling protein.
It is now almost a truism to say “that regardless of the initial cause of renal disease the actual loss of kidney function is nearly always due to the process of unrestrained accumulation of scar proteins in the kidney called fibrosis”. None the less it remains true and often important to restate - particularly as the process of fibrosis occurs in many organs in the body including, the lung, liver, heart, pancreas, arteries and of course the kidney - there are no medicines that are designed directly to block fibrosis.
SWTIRR has been interested in the production of the ECM that make up the scar in the fibrosing kidney, particularly fibronectin. In 2006 we published a paper on the importance of p38 MAP kinase in the production of fibronectin from human renal epithelial cells. Since that time our interest in fibronectin has focussed on the selective production of one particular isoform, or splice variant.
Different splice variants are produced by the process of alternative splicing, a process which effectively allows for the production of more than one protein from a single gene. Nearly 80% of human genes are subject to alternative splicing and this is part of the reason that on completion of the human genome project it was discovered that as a species we have considerably fewer genes than were predicted. Alternative splicing allows for the assembly or splicing together of different exons from the genomic DNA to form a range of different proteins.
In the case of fibronectin there are at least three different potential splice site and we are currently investigating the regulation of splicing that includes the Extra Domain A (EDA) into the protein. There is increasing evidence for the role of EDA fibronectin in fibrotic disease in different organs as it appears to have a particularly strong pathological role. Our current work has identified role for the SR family of proteins and PI 3 kinase in the regulation of EDA inclusion in human proximal tubule epithelial cells.
Currently Dr Sima Shirali is working to try and identify how these different signalling molecules interact to regulate the production of EDA+ fibronectin and to identify stages in the process that could be targeted by drug therapy to prevent it.