Role of I kappa B kinase-2 (IKK2) and p38 mitogen activated protein kinase (MAPK) in glomerulonephritis

Lead Research Organisation: Imperial College London
Department Name: Research Office

Abstract

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Publications

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Ma TK (2017) Targeting the tyrosine kinase signalling pathways for treatment of immune-mediated glomerulonephritis: from bench to bedside and beyond. in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

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McAdoo SP (2011) Fostamatinib Disodium. in Drugs of the future

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McAdoo SP (2014) Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN. in Journal of the American Society of Nephrology : JASN

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Smith J (2010) A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis. in Journal of the American Society of Nephrology : JASN

 
Description impact on researchers
Geographic Reach North America 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Clinical Research Training Fellowship
Amount £211,788 (GBP)
Funding ID G0901997 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2010 
End 08/2013
 
Description Commerical Clinical Trial Grant
Amount £6,000,000 (GBP)
Organisation Rigel Pharmaceuticals 
Sector Private
Country United States
Start 12/2014 
End 07/2017
 
Description Industrial grant from Baxter Innovation
Amount £1,347,000 (GBP)
Organisation Baxter Innovations GmbH 
Sector Private
Country Austria
Start 08/2006 
End 06/2012
 
Description Making Every Kidney Count Programme Grant
Amount £414,000 (GBP)
Funding ID SP/MEKC/5/2014 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2015 
End 01/2019
 
Title treatment of established experimental glomerulonephritis 
Description We have optimised the use of nephrotoxic nephritis in Wistar Kyoto rats. In our design, anti-inflammatory drugs, including oral administration of small molecule inhibitors, was started after onset of glomerulonephritis. The findings of the model can be related to human diseases, for example, both the rat model and human diseases are assessed by proteinuria, creatinine clearance and renal histopathology. The same mechanistic biomarker (monocyte chemottractant protein-1) were applicable in both urine and renal tissues in the rat model and human disease. Finally, we have a related renal cell culture system, in which, the concentration of kinase inhibitor to inhibit MCP-1 synthesis is similar to the plasma concentration of the inhibitor in the rat model in vivo. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2008 
Provided To Others? Yes  
Impact The model has now been used by the industries in pre-clinical development of anti-inflammatory drugs. 
 
Description Rigel Pharmaceuticals, South San Francisco, U.S.A. 
Organisation Rigel Pharmaceuticals
Country United States 
Sector Private 
PI Contribution We have provided the specific models in this collaborative study: models of kidney diseases in vivo (nephroxic nephritis, experimental autoimmune glomerulonephritis, experimental autoimmune vasculitis, experimental renal allograft rejection) and in vitro culture of renal cells and macrophages. We have been successful in obtaining an MRC training fellowship application (outcome in 2010) to investigate the mechanism of action and potential clinical translation, and a Kidney Research UK programme grant to study Syk as a novel therapeutic target in rejection of kidney transplant.
Collaborator Contribution We have obtained the specific Syk inhibitors and the critical in house results for early development in clinical treatment of renal diseases.
Impact We have just published our result in the Journal of American Society of Nephrology Publication and Kidney International
Start Year 2007
 
Description Roche Palo Alto 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution We have also showed our collaboration a novel use of a rat model to assess the effect of an anti-inflammatory drug in treatment of established renal disease. This is very useful to the research and development programme of the industry. For example, some novel treatment of arthritis may be tested in our in vivo model for future application in renal diseases.
Collaborator Contribution Roche has provided the specific inhibitors for p38 MAPK and IKK2 in this study. In addition, they provide in the confidential in house research data for the design of this project. Finally, their research team did the measurement of active drug concentration in the plasma from our in vivo study
Impact We found that p38 MAPK is a novel therapeutic target in glomerulonephritis. This resulted in the publication of our full manuscript in Journal of American Society of Nephrology in 2007 (in the publication list). This is part of rational basis of our clinical translational programme to use small molecule kinase inhibitors as novel treatment of renal diseases.
 
Description Invited presentation to pharmaceutical industries: Roche, Baxter, Rigel 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact From our published work, the pharmaceutical industries invited me to give seminars and discussed research strategies for development of new treatment for renal diseases.

Yes, the key impacts are: (1) stimulated the industry to commit clinical development of novel anti-inflammatory treatment of glomerulonephritis, (2) development of novel anti-cytokine therapies with fully funded industrial collaboration grants.
(3) recent development of an international multi-centre randomised controlled trial of SYK inhibitor in IgA nephropathy
Year(s) Of Engagement Activity 2006,2007