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
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Publications
Kim MJ
(2012)
Spleen tyrosine kinase is important in the production of proinflammatory cytokines and cell proliferation in human mesangial cells following stimulation with IgA1 isolated from IgA nephropathy patients.
in Journal of immunology (Baltimore, Md. : 1950)
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
McAdoo SP
(2011)
Fostamatinib Disodium.
in Drugs of the future
McAdoo SP
(2014)
Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN.
in Journal of the American Society of Nephrology : JASN
McAdoo SP
(2015)
Correlation of disease activity in proliferative glomerulonephritis with glomerular spleen tyrosine kinase expression.
in Kidney international
Sheryanna A
(2007)
Inhibition of p38 mitogen-activated protein kinase is effective in the treatment of experimental crescentic glomerulonephritis and suppresses monocyte chemoattractant protein-1 but not IL-1beta or IL-6.
in Journal of the American Society of Nephrology : JASN
Smith J
(2010)
A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis.
in Journal of the American Society of Nephrology : JASN
Turner CM
(2014)
Is the inflammasome a potential therapeutic target in renal disease?
in BMC nephrology
| 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 |