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

Lead Research Organisation: University College London
Department Name: Institute of Child Health

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Dessapt-Baradez C (2014) Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease. in Journal of the American Society of Nephrology : JASN

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Gnudi L (2015) Vascular growth factors play critical roles in kidney glomeruli. in Clinical science (London, England : 1979)

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Gnudi L (2016) Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms. in Trends in endocrinology and metabolism: TEM

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Henderson DJ (2018) Planar cell polarity in organ formation. in Current opinion in cell biology

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Huang JL (2016) Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases. in Journal of the American Society of Nephrology : JASN

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Huang JL (2013) Angiogenesis and autosomal dominant polycystic kidney disease. in Pediatric nephrology (Berlin, Germany)

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Papakrivopoulou E (2014) Planar cell polarity and the kidney. in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

 
Description Kidney Research UK Post-doctoral fellowship to Dr Elisavet Vasilopoulou
Amount £200,631 (GBP)
Funding ID PDF8/2015 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 08/2018
 
Description Undergraduate Vacation Studentship to Miss Renata Assuncao De Sousa Brites
Amount £1,600 (GBP)
Organisation Physiological Society 
Sector Learned Society
Country United Kingdom
Start 06/2015 
End 09/2015
 
Title Podocyte thymosin-beta4 conditional knock-out mice 
Description Mice lacking thymosin-beta4 specifically in the podocyte 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact We are currently using this animals to test the role of podocyte thymosin-beta4 in glomerular development and disease. 
 
Description Dr Mike Robson 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative studies investigating thymosin-beta 4 in glomerular disease
Collaborator Contribution Intellectual input, provision of anti-glomerular basement membrane serum for animal studies.
Impact Oral and poster presentations at international meetings.
Start Year 2012
 
Description Professor Alan Salama 
Organisation Royal Free Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Assessment of thymosin-beta4 expression in human samples from patients with glomerular disease.
Collaborator Contribution Provision of human samples from patients with glomerular disease.
Impact None to date
Start Year 2015
 
Description Professor Christian Kupatt 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Country Germany 
Sector Academic/University 
PI Contribution Experiments assessing whether adeno-associated virus for thymosin-beta4 improves the progression of glomerular disease.
Collaborator Contribution Provision of adeno-associated virus for thymosin-beta4
Impact None to date
Start Year 2016
 
Description Professor Paul Riley 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative studies investigating thymosin-beta 4 in kidney development and disease
Collaborator Contribution Intellectual input, provision of thymosin-beta 4 knock-out mice.
Impact Oral and poster presentations at international meetings, generation of podocyte thymosin-beta 4 knock-down mice.
Start Year 2011
 
Description Career development session at the 64th Annual Meeting of the British Microcirculation Society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Part of panel examining scientific career development at the 64th Annual Meeting of the British Microcirculation Society. General discussion and Q and A session with audience members.

Follow-up discussions with audience members regarding career advice
Year(s) Of Engagement Activity 2014
 
Description Interview regarding our study on vascular growth factors in polycystic kidney disease 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Interview with communications consultant at Kidney Research UK about our work on vascular growth factor therapy in polycystic kidney disease - led to an article in the Journal of Renal Nursing
Year(s) Of Engagement Activity 2015
URL http://www.magonlinelibrary.com/doi/abs/10.12968/jorn.2015.7.4.196?journalCode=jorn
 
Description Interview with the scientist magazine 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interview about our study on vascular growth factor therapy for polycystic kidney disease.
Year(s) Of Engagement Activity 2015
URL http://www.the-scientist.com/?articles.view/articleNo/43550/title/Rethinking-Lymphatic-Development/
 
Description Kidney Research UK donors visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact Around 10 donors from Kidney Research UK attended an afternoon of talks followed up a laboratory tour at the Institute of Child Health.
Year(s) Of Engagement Activity 2016
 
Description Press release for polycystic kidney disease paper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Numerous press releases from UCL, Great Ormond Street, University of Manchester, Kidney Research UK and Kids Kidney Research describing our work on vascular growth factor therapy for polycystic kidney disease. This was picked up by multiple international news outlets leading to numerous enquires about our work.
Year(s) Of Engagement Activity 2015
URL http://www.gosh.nhs.uk/news/latest-press-releases/2015-press-release-archive/researchers-uncover-new...
 
Description UK renal research report launch at the House of Lords 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact I attended the launch of the Kidney Research UK renal research report at the House of Lords - an opportunity to discuss the importance of kidney research with politicians and other policymakers.
Year(s) Of Engagement Activity 2016
URL http://www.kidneyresearchuk.org/news/house-of-lords