The role of podocyte thymosin-beta4 in the healthy and diseased glomerulus

Long term severe kidney disease can only be treated by dialysis or transplantation, and the number of people needing this type of support has doubled in frequency over the last ten years in the UK. It now affects 100 people per million population and is rising. One key feature of kidney disease is disruption to the filtration unit which is a highly complex structure created from several different cell types. One of these cells, the podocyte, has a highly branched shape which is essential for its function. Disruption to this shape, a feature of many childhood and adult kidney diseases such as minimal change disease and diabetic kidney disease, leads to loss of protein in the urine and if persistent to end stage kidney disease. Therefore, understanding how podocyte shape develops in the first place, could provide the knowledge necessary to restore it after injury and thus greatly improve treatment of many kidney diseases. In this project, I will study the role of a molecule called thymosin-beta4 which is highly expressed in podocytes and involved in maintaining cell shape; key to the development of other organs such as the heart and currently being investigated in clinical trials as a potential treatment for diseases such as wound healing and myocardial infarction. In this New Investigator award, I will look at what thymosin-beta4 does in the developing and mature filtration barrier of the kidney and in an experimental model of kidney disease. If modulation of thymosin-beta4 slows the progression of kidney disease, it could be a new exciting therapeutic avenue for these patients in the future.

Research objectives: The objectives of these studies are (i) to determine the role of podocyte thymosin-beta4 in the developing and mature healthy glomerulus using transgenic mice and cultured cells. (ii) determine if modulation of thymosin-beta4 attenuates progression of glomerular disease, hence raising the possibility that thymosin-beta4 could improve the health of kidney patients. (iii) assess the relative contribution of podocytes and other renal sites of thymosin-beta4 in the progression of glomerular disease.

Experimental Design: I will utilise global null-mutants and specific knock down of thymosin-beta4 in the podocyte using floxed thymosin-beta4 animals bred with doxycycline inducible podocyte-specific Cre recombinase mice and will assess changes in the structure and molecular biology of the glomerulus. Moreover, using the above transgenic animals, I will determine whether lack of thymosin-beta4 alters progression of immune-mediated and adriamycin-induced glomerular diseases. These are good models of human pathologies and it will be important to identify how the balance of thymosin-beta4 in different parts of the kidney affects the course of disease because this will influence how targetted therapies need to be developed.

Application and Exploitation: My studies will define the function of thymosin-beta4 in the kidney glomerulus which will lead to high-impact publications in scientific journals. In addition, it could lead to the design of new therapies for human renal disease. If this is the case, then thymosin-beta4 has the potential to impact on society by improving the quality of life of patients with kidney disease as well as a major economic impact by reducing the number on expensive dialysis regimens or needing a kidney transplant.

This research has the potential to discover a new treatment strategy for glomerular disease. Glomerular disease, resulting in defective filtration and proteinuria, accounts for many cases of end-stage renal failure (ESRF); a devastating condition requiring life-long dialysis or transplantation. Over the last decade an epidemic of ESRF has occurred, linked to increased obesity and diabetes with a doubling in the UK to 100/million population; costs in the USA have now increased to around $30 billion/annum placing an extremely high burden on healthcare resources. Therefore new therapies preventing glomerular disease are vitally important and have the potential to impact on society by improving the quality of life of patients with kidney disease and have an economic impact by reducing the impact of ESRF and saving healthcare costs. If thymosin-beta4 proves to be a potential therapeutic target in glomerular disease, this will be of potential interest to drug companies. At least one company, Regenerx, has taken thymosin-beta4 into clinical trials for acute myocardial infarction and dermal and ophthalmic wound healing trials (www.regenerx.com), and similar strategies could be used for renal disease.

This New Investigator Award will also contribute to the progression of Dr. Long's own academic career. This will allow me to develop my own group of researchers, facilitating my academic progression through to Lecturer, Senior Lecturer and Professorship over the next 10 years. During the grant, the researcher employed will also be trained in important skills not only in the laboratory, but also academically. This will achieved not only through on-the-job training, but also courses provided for researchers from UCL and ICH.

Other beneficiaries will include the collaborative team involved in the research both within my Institution and with centres in North America. All of the partners have already contributed reagents or mice along with intellectual input into the design of the grant and their contributions will be key to ensuring the research is successful. Professor Paul Riley (ICH) has a large group working mainly on heart development and has Industry links; Professor Susan Quaggin (Toronto) developed a specific mouse strain and collaborates with researchers around the world to develop new models for important kidney diseases; and Professor Agnes Fogo is a world expert on fibrosis and is at the forefront of designing new technologies to treat patients.

The results of these studies will be of interest to renal researchers as not only we will understand more about thymosin-beta4 in the kidney, but the data will enhance our understanding of the role of this important molecule in kidney development and disease, but may lead to novel insights into the biology of the glomerular filtration barrier. We may also identify potential new functions of thymosin-beta4 and generate new molecular tools which will be of interest to other researchers in other fields, such as vascular biology.