Characterisation of the LRRK2 protein kinase, mutated in inherited Parkinson s disease

Lead Research Organisation: University of Dundee
Department Name: College of Life Sciences

Abstract

Parkinson?s disease is a serious degenerative brain disorder resulting in tremors and abnormally slow movements in patients. The disease has no cure and is a major cause of disability and early death worldwide. A recent breakthrough has lead to the discovery that mutations in a gene called LRRK2 can cause Parkinson?s disease in humans. The LRRK2 gene encodes for an enzyme. It is not known how the LRRK2 enzyme works in human brains and how its mutation causes Parkinson?s disease. The purpose of this application is to undertake studies that define how LRRK2 works in the brain. We also aim to learn how mutations in LRRK2 might cause Parkinson?s disease. Moreover, this research will provide knowledge and methodology to facilitate the development of new drugs that target the LRRK2 enzyme for the treatment of Parkinson?s disease ? and possibly dementias such as Alzheimer?s disease.

Technical Summary

There has been much interest raised by the recent discovery that different autosomal dominant point mutations within the gene encoding for the Leucine Rich Repeat protein Kinase-2 (LRRK2), predispose humans to develop late-onset Parkinson?s disease (PD), with a clinical appearance indistinguishable from idiopathic PD. Mutations in LRRK2 are relatively frequent, accounting for 5-10% of familial PD, and are also found in a significant proportion of sporadic PD cases. Little is known about how LRRK2 is regulated in cells, what are its physiological substrates and how mutations in LRRK2 cause or increase risk of PD. The most prevalent mutant form of LRRK2 comprises an amino acid substitution of Gly2019 within the kinase domain that enhances the kinase activity of LRRK2 three-fold. The purpose of this application would be to build upon ongoing LRRK2-based research within the MRC Protein Phosphorylation Unit and GlaxoSmithKline. We will focus on studying the expression, activity and function of endogenous LRRK2 protein, especially in primary neuronal cells and tissues. We would study which agonists and upstream signalling pathways control LRRK2 activity and undertake experiments to assess the role of LRRK2 in phosphorylating moesin and related proteins that we have recently discovered to be efficiently phosphorylated by LRRK2 in vitro. Overall the aim of this research is to better define the cellular roles of LRRK2 and obtain insight into how LRRK2 mutations might contribute to Parkinson?s disease and other Neurodegenerative diseases, including Alzheimer?s disease. This work would effectively utilise the strengths to be gained through academic/industrial collaboration to cement and rapidly exploit an area of new scientific breakthrough in relation to neurodegenerative diseases. It would also provide the pharmaceutical industry with better knowledge and reagents to prosecute LRRK2 as a drug target and to test the efficacy and selectivity of drugs developed against this enzyme.

Publications

10 25 50
 
Description A systematic investigation into the pathogenesis and course of Paskinson's syndrome
Amount £300,000 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 01/2010 
End 01/2015
 
Description Assessment of LRRK2 activity in G2385R carriers
Amount £57,771 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2018 
End 07/2019
 
Description Equipment grant
Amount £260,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Exploiting Ser910/935 phosphorylation and 14-3-3 binding to develop biomarkers for LRRK2 activity
Amount £120,431 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2010 
End 01/2012
 
Description Genome wide screens to uncover novel upstream regulators of LRRK2
Amount £305,944 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start  
 
Description Impact of Shared Crohn's disease
Amount £55,444 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2018 
End 10/2019
 
Description Industrially supported Postdoc collaboration
Amount £303,948 (GBP)
Organisation Johnson & Johnson 
Department Janssen Pharmaceuticals
Sector Private
Country United States
Start 01/2011 
End 01/2014
 
Description J MacDonald Menzies
Amount £177,000 (GBP)
Organisation J Macdonald Menzies Charitable Trust 
Sector Charity/Non Profit
Country Unknown
Start  
 
Description LEAPS Award to identify LRRK2 substrates
Amount $1,500,000 (USD)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 02/2012 
End 01/2015
 
Description Lanston Award
Amount £17,582 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2018 
End 12/2019
 
Description Mass-spectrometry based global analysis of protein phosphorylation in cells and tissue extracts with altered PINK1 catalytic activity: a novel screen for PINK1 substrates
Amount £84,945 (GBP)
Funding ID H-0901 
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 01/2012
 
Description PhD Studentship
Amount £146,000 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 01/2015
 
Description Project Grant
Amount £56,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2012 
End 01/2013
 
Description Project Grant
Amount £161,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2011 
End 01/2013
 
Description Project grant
Amount £93,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start  
 
Description Project grant
Amount £63,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start  
 
Description Project grant
Amount £23,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start  
 
Description Project grant
Amount £122,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start  
 
Description QQ Renewal
Amount £25,590,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description Rab LEAPs Renewal
Amount £332,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 08/2018 
End 07/2020
 
Description Rapid Innovation Award - Identification of substrates and development of a cell-based assay for LRRK2
Amount £46,500 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2009 
End 01/2010
 
Description Renewal of Division of Signal Transduction Therapy Unit
Amount £7,200,000 (GBP)
Organisation Dundee Signal Transduction Therapy (DSTT) Consortium 
Sector Academic/University
Country United Kingdom
Start  
 
Description Renewal of MRC Protein Phosphorylation and Ubiquitylation Core Funding
Amount £24,000,000 (GBP)
Funding ID Purchase Order Number: 4050295594 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2013 
End 03/2018
 
Description Renewal of MRC-PPU quinquenial funding
Amount £23,100,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2013 
End 03/2018
 
Description Studentship
Amount £92,000 (GBP)
Organisation Parkinson's UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Tools Development
Amount £83,244 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2018 
End 09/2020
 
Description Tools and Animal Models
Amount £54,902 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 07/2018 
End 12/2019
 
Description Understanding LRRK2 2 year project grant to fund postdoc in lab
Amount £130,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2010 
End 01/2012
 
Description small project grant to work on LRRK2 Kinase
Amount £29,000 (GBP)
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 06/2013 
End 05/2014
 
Title Development of novel state of the art phospho-specific Rabbit monoclonal antibodies to studdy LRRK2 mediated phosphorylation of Rab proteins in Parkinson's disease 
Description Mutations that activate the LRRK2 (leucine-rich repeat protein kinase 2) protein kinase predispose to Parkinson's disease, suggesting that LRRK2 inhibitors might have therapeutic benefit. Our recent work has revealed that LRRK2 phosphorylates a subgroup of 14 Rab proteins, including Rab10, at a specific residue located at the centre of its effector-binding switch-II motif. In the present study, we analyse the selectivity and sensitivity of polyclonal and monoclonal phospho-specific antibodies raised against nine different LRRK2-phosphorylated Rab proteins (Rab3A/3B/3C/3D, Rab5A/5B/5C, Rab8A/8B, Rab10, Rab12, Rab29[T71], Rab29[S72], Rab35 and Rab43). We identify rabbit monoclonal phospho-specific antibodies (MJFF-pRAB10) that are exquisitely selective for LRRK2-phosphorylated Rab10, detecting endogenous phosphorylated Rab10 in all analysed cell lines and tissues, including human brain cingulate cortex. We demonstrate that the MJFF-pRAB10 antibodies can be deployed to assess enhanced Rab10 phosphorylation resulting from pathogenic (R1441C/G or G2019S) LRRK2 knock-in mutations as well as the impact of LRRK2 inhibitor treatment. We also identify rabbit monoclonal antibodies displaying broad specificity (MJFF-pRAB8) that can be utilised to assess LRRK2-controlled phosphorylation of a range of endogenous Rab proteins, including Rab8A, Rab10 and Rab35. The antibodies described in the present study will help with the assessment of LRRK2 activity and examination of which Rab proteins are phosphorylated in vivo These antibodies could also be used to assess the impact of LRRK2 inhibitors in future clinical trials. 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? Yes  
Impact All companies and researchers investigating LRRK2 are now using our technology. A company called Denali has just launched the first clinical trials for LRRK2 inhibitors and are using our reagents for their monitoring efficacy of LRRK2 inhibitors. Many other companies are likely to follow suit 
 
Title new assay to quantify LRRK2 kinase activity 
Description We have developped a new assay to quamtify LRRK2 kinase activity 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Many groups worldwide are using our assay for LRRK2 and the MRC patented this assay in 2008. Further data has been added to MRC patent this year to strengthen it 
 
Description Became a member of Wellcome Trust-MRC funded UK Parkinson's disease initiative 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution We undertake the biochemical and siganlling analysis of this part of the collaboration
Collaborator Contribution This has provided us with vital clinical links to the best UK Pakinson's disease clinical researchers (Nick Wood, Tony Schapiro and John Hardy) at the world faous institute of Neurology. Alex Withworth from Sheffield University is also a member of this consortium. This is the first time in the UL that a large group of researchers with complementary expertise has been brought together to combat Parkinson's disease
Impact This collaboration has just started but numerous collaborations are underway and we hope to have more tangiable outputs to report soon
Start Year 2010
 
Description DSTT 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation Johnson & Johnson
Department Janssen Pharmaceutica
Country Global 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation Merck
Department Merck Serono
Country Germany 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution All the Programme Leaders in the MRC Protein Phosphorylation Unit have participated in a major collaboration with the pharmaceutical industry since 1998, termed The Division of Signal Transduction Therapy. From July 2003 to July 2008, the participating pharmaceutical companies were AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck and Co, Merck-Serono and Pfizer. The collaboration was renewed for a further four years in July 2008 with five of these companies (Merck and Co leaving the consortium at this time). This collaboration was renewed for an unprecedented fourth time in July 2013 for a further four years with six pharmaceutical companies (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Janessen Pharmaceutica), Merck-Serono and Pfizer. Each of the six companies pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease. For more information see http://www.ppu.mrc.ac.uk/overview/DSTT.php
Collaborator Contribution Benefits from DSTT collaboration The MRC-PPU benefits in many ways as a result of the DSTT research collaboration. 1. It provides an obvious translational outlet to enable our PIs to exploit their research findings. For example, any PI within the MRC-PPU can rapidly let all six pharmaceutical companies know about any new potential exciting research finding that they have made or any drug target that they have identified or validated. This can lead to major collaborations and stimulate one or more of the pharmaceutical companies to initiate a new drug discovery programme. 2. The research support received from this collaboration is invested in the PPU PIs research programmes and provides additional support to several of our Unit's Scientific service teams including our protein production teams, antibody generation team and cloning team. 3. We obtain key reagents including novel inhibitors, genetically modified cell or mice models from our DSTT pharmaceutical company collaborators. 4. The pharmaceutical companies we collaborate with provide us with important knowledge on the most critical research issues of the day for their drug development programmes. This feedback and industry perspective is extremely useful and helps maximise our overall competitiveness. It ensures that the drug discovery research programmes of the PPU PIs are focussed on addressing the most important questions for better understanding and treating disease. 5. The DSTT collaboration greatly benefits our students and postdocs by providing experience in working with industry via their direct involvement in collaborative experiments with pharmaceutical companies. This provides them with a unique insight into the high quality cutting edge research that is taking place within pharmaceutical companies and gives them an awareness of potential careers in industry. This is particularly important given that one of our main priorities is to train tomorrow's industrial researchers and ensure that the future workforce has the high quality scientific and research support skills that the UK economy will be dependent on.
Impact During the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
 
Description DSTT renewal 2016 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact uring the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description DSTT renewal 2016 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact uring the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description DSTT renewal 2016 
Organisation Merck
Department Merck Serono Ltd
Country United Kingdom 
Sector Private 
PI Contribution Boehringer-Ingelheim, GlaxoSmithKline and Merck-Serono - each company pays £600000 per annum over the four year period. The aim of the collaboration is to help the pharmaceutical companies accelerate the development of drugs that inhibit protein and lipid kinases and phosphatases with therapeutic potential for the treatment of disease.
Collaborator Contribution The MRC-PPU benefits in many ways as a result of the DSTT research collaboration.
Impact uring the collaboration, the Unit has helped to launch and/or accelerate many drug discovery programmes, some of which have entered human clinical trials. The collaboration led the Unit to develop the technology of protein kinase profiling which has developed into an industry worth over £100 million per annum. It also led to the creation of the European Division of Upstate Incorporated in Dundee which currently employs about 50 people. The Unit's first publication on protein kinase profiling was named in 2009 by the Institute for Scientific Information, Philadelphia as Europe's most cited paper in the field of Cel Biology from 1996-2007, with over 2,200 citations. During the collaboration, the Unit has filed 36 patents and 30 licenses have been taken up by the pharmaceutical industry. The DSTT is widely regarded as a model of how academia and industry should interact for which it received a Queen's Anniversary Award for Higher Education which was presented by the Queen and Duke of Edinburgh at Buckingham Palace in February 2006. GlaxoSmithKline have announced that their BRAF protein kinase inhibitor Dabrafenib (Tafinlar), has been approved by both the European Commission and the United States Food and Drug Administration for the treatment of unresectable or metastatic melanoma associated with the BRAF V600E mutation. Unresectable melanoma is that which cannot be removed by surgery, while metastatic melanoma is that which has spread to other parts of the body. The new drug was developed employing BRAF enzymes generated by researchers in the Division of Signal Transduction Therapy (DSTT) in the College of Life Sciences at Dundee.
Start Year 2016
 
Description Kevin O 
Organisation University of Cambridge
Department Department of Anglo-Saxon, Norse and Celtic
Country United Kingdom 
Sector Academic/University 
PI Contribution provided genetically modified mice, reagents, technology and advice
Collaborator Contribution Undertook blood pressure measuremnts in mice and other physiological experiments
Impact Zhang, J., Siew, K., Macartney, T., O'Shaughnessy, K. M. and Alessi, D. R. (2015). Critical role of the SPAK protein kinase CCT domain in controlling blood pressure. Hum Mol Genet 24, pp. 4545-4558 Rafiqi, F. H., Zuber, A. M., Glover, M., Richardson, C., Fleming, S., Jovanovic, S., Jovanovic, A., O'Shaughnessy, K. M. and Alessi, D. R. (2010). Role of the WNK-activated SPAK kinase in regulating blood pressure. EMBO Mol Med 2, pp. 63-75
Start Year 2009
 
Description Nathanael Gray Chemical Biology 
Organisation Dana-Farber Cancer Institute
Department Department of Cancer Biology
Country United States 
Sector Academic/University 
PI Contribution We undertake the biological characterization of tool compounds that the Gray lab generates that target the enzymes we are working with
Collaborator Contribution We have thus far developed some state of the art new inhibitors that can be used to dissect biological roles of the Parkinson's disease LRRK2 protein kinase
Impact We have thus far co-authored 7 research papers and obtained two major Michael J Fox Foundation grant award to understand how mutations in LRRK2 cause Parkinson's disease
Start Year 2010
 
Description New programme to Develp IRAK inhibitors 
Organisation Dana-Farber Cancer Institute
Department Department of Cancer Biology
Country United States 
Sector Academic/University 
PI Contribution Using funding from this grant application the lab of Philip Cohen has generated knock-in mice expressing the catalytically inactive IRAK1[D358A] mice. We have exploited cells from these mice to establish that IRAK1 is the protein kinase that mediates the IL-1-stimulated activation of the E3 ubiquitin ligase Pellino 1 in fibroblasts but not in bone marrow-derived macrophages stimulated with Toll-Like Receptor (TLR) agonists, where it is activated by the IKK-related kinases. We have also established that IRAK1 catalytic activity is not required for the activation of the transcription factor NFkappaB or MAP kinases by either IL-1 or ligands that activate TLRs, and that IRAK1 catalytic activity is also not required for the production of pro-inflammatory cytokines in macrophages stimulated with TLR agonists. These results have recently been published :
Collaborator Contribution Using funding from this grant application the lab of Philip Cohen has generated knock-in mice expressing the catalytically inactive IRAK1[D358A] mice. We have exploited cells from these mice to establish that IRAK1 is the protein kinase that mediates the IL-1-stimulated activation of the E3 ubiquitin ligase Pellino 1 in fibroblasts but not in bone marrow-derived macrophages stimulated with Toll-Like Receptor (TLR) agonists, where it is activated by the IKK-related kinases. We have also established that IRAK1 catalytic activity is not required for the activation of the transcription factor NFkappaB or MAP kinases by either IL-1 or ligands that activate TLRs, and that IRAK1 catalytic activity is also not required for the production of pro-inflammatory cytokines in macrophages stimulated with TLR agonists. These results have recently been published : Goh, E.T.H., Arthur,J.F.C., Cheung, P.C.F., Akira, S., Toth, R. and Cohen, P. (2011) Identification of the protein kinases that activate the E3 ubiquitin ligase Pellino 1 in the innate immune system. Biochem. J. published on-line October 18th This study led to a collaboration with Nathanael Gray at Harvard University, USA to develop inhibitors of IRAK1. Philip is also trying to persuade MRC Technology and Major Pharma companies to try and deveopIRAK1 inhibitors
Impact Intensive ork is in progress to develop IRAK1 inhibitors and hoepfully we will have more news to report on this next year.
Start Year 2010
 
Description Role of LRRK2 phosphorylating Rab GTPase in Parkinson's 
Organisation Max Planck Society
Department Max Planck Martinsried
Country Germany 
Sector Academic/University 
PI Contribution I was the PI of a major MJFF collaboration that lead to the discovery that LRRK2 Parkinson's kinase's phosphorylates and inhibits multiple Rab GTPases. This was very exciting as this was the first physiological substrate for LRRK2 to be identified. Our laboratory coordinated the project and laed on many of the key experiments in this project
Collaborator Contribution The group of Matthias Mann undertook all the mass spectrometer experiments in this project and Susan Pfeffer's laboratory is undertaking the cell biology analysis
Impact Grant Income that funds research of two postdoctoral researchers in my lab
Start Year 2015
 
Description Role of LRRK2 phosphorylating Rab GTPase in Parkinson's 
Organisation Stanford University
Department Department of Biochemistry
Country United States 
Sector Academic/University 
PI Contribution I was the PI of a major MJFF collaboration that lead to the discovery that LRRK2 Parkinson's kinase's phosphorylates and inhibits multiple Rab GTPases. This was very exciting as this was the first physiological substrate for LRRK2 to be identified. Our laboratory coordinated the project and laed on many of the key experiments in this project
Collaborator Contribution The group of Matthias Mann undertook all the mass spectrometer experiments in this project and Susan Pfeffer's laboratory is undertaking the cell biology analysis
Impact Grant Income that funds research of two postdoctoral researchers in my lab
Start Year 2015
 
Description Role of LRRK2[R1441G] mutations in Parkinson's 
Organisation University of Hong Kong
Department Li Ka Shing School of Medicine
Country Hong Kong 
Sector Academic/University 
PI Contribution The group of Prof Ho have generated an LRRK2[R1441G] knock-in mouse that mimics one of the major disease causing mutations in human Parkinson's patients. We have initiated a major collaboration to discover how this mutation induces phosphorylation of Rab isoforms by LRRK2 and work out how this is linked to development of Parkinson's disease.
Collaborator Contribution Providing LRRK2[R1441G] knock-in mouse and helping with some of the experiments
Impact none as yet-but we should have some interesting data that should be published in 2016
Start Year 2015
 
Description We initiated a major Collaboration with Nathanael Gray at the Dana Farber Cancer insititute to develop LRRK2 inibitors 
Organisation Dana-Farber Cancer Institute
Department Department of Cancer Biology
Country United States 
Sector Academic/University 
PI Contribution We were able to help Nathanael Gray develop a potent LRRK2 inhibitor and we undertook all the in vivo testing of this inhibitor to demonstrate that it specifically inhibited LRRK2 in vivo
Collaborator Contribution I as well as my colleagues at the MRC-PPU have many additional collaborations with Nathaneal Gray who is an amazing chemical biologist. The work he is doing has the possibility to greatly aid our research. We are even now trying to recruit him to Dundee!
Impact Grant application 2011-2013 Michael J. Fox Foundation for Parkinson's Research (MJFF) Project Grant, (Joint with Nathanael Gray [Main Applicant]), Dundee MRC-PPU share US$254,400 Plus the following 2 papers 181. Deng, X., Dzamko, N., Prescott, A.R., Davies, P., Liu, Q., Yang, Q., Lee, J.D., Patricelli, M.P., Nomanbhoy, T.K., Alessi, D.R. and Gray, N.S. (2011) Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2. Nature Chemical Biology 7, 203-205. Zhang, T., Inesta-Vaquera, F., Niepel, M., Zhang, J., Ficarro, S., Machleidt, T., Xie, T., Marto, J.A., NKim, N., Sim, T., Laughlin, J.D., Park, H., LoGrasso, P. V., Patricelli, M., Nomanbhoy, T.K., Sorger, P/K., Alessi, D.R. and Gray, N.S. (2011) Discovery of potent and selective covalent inhibitors of JNK. Chemistry & Biology In the Press
Start Year 2009
 
Title LRRK2 assay 
Description A method for identifying a compound expected to be useful in modulating a LRRK2 protein kinase activity. 
IP Reference EP2132326 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact Novel and improved (earlier filing-A813/2087) substrate for LRRK2, a kinase implicated in Parkinson's Disease.
 
Title LRRK2 assay 
Description A method for identifying a compound expected to be useful in modulating a LRRK2 protein kinase activity. 
IP Reference EP2132326 
Protection Patent granted
Year Protection Granted 2009
Licensed No
Impact Novel and improved (earlier filing-A813/2087) substrate for LRRK2, a kinase implicated in Parkinson's Disease.
 
Title PDK1 (the kinase that phosphorylates and activates PKB) nucleotide and peptide sequence; methods of purifying and expressing PDK1 and screens to identify PDK1 modulators. 
Description Assay and use of PDK1 inhibitors 
IP Reference US2007196883 
Protection Patent granted
Year Protection Granted 2007
Licensed Yes
Impact Patent granted, Consortium licence (to Pharma companies in Dundee Collaboration)
 
Title PDK1 crystal structure 
Description Assay of PDK1. 
IP Reference JP2005323611 
Protection Patent granted
Year Protection Granted
Licensed Yes
Impact Application includes the co-ordinates, X-ray data, crystallisation conditions and the cDNA construct., Patent granted,
 
Title TAPP1 Clinical Function 
Description Discovery and use of TAPP1 and TAPP2. 
IP Reference US2007054328 
Protection Patent granted
Year Protection Granted 2007
Licensed No
Impact "TAPP1- PTPL1 interaction is therefore identified as a target to find therapeutics for disorders such as diabetes that are associated with deregulated tyrosine kinase signalling., National phase"
 
Title WNK assay 
Description Activation and assay of the WNK-acttvated SPAK and OSR1 kinases 
IP Reference US2008286809 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact WNK (With No lysine Kinase) kinases have been implicated as a potential target to treat hypertension. Mutations in the human genes encoding WNK1 and the related protein kinase WNK4, are the cause of Gordon's hypertension syndrome. Application discloses the naturally occurring substrates for WNK1 and 4 and describes an assay to identify modulators of their activity., National phase
 
Title LRRK2 assay 
Description New optimised assay to assess LRRK2 function 
Type Support Tool - For Medical Intervention
Current Stage Of Development Initial development
Year Development Stage Completed 2009
Development Status Under active development/distribution
Impact Patent filed by MRC. Many companies using this assay for drug screening programs to develop LRRK2 inhibitors for the treatment of Parkinson's disease 
 
Description 20 Year Celebration of the DSTT 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact During an event at Dundee's recently opened V&A museum to celebrate the 20 year anniversary of the DSTT I gave an interview with STV news.
Year(s) Of Engagement Activity 2018
 
Description 7 2017 CDKL5 Forum Meeting - Boston, November 29-30 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Stimulate research and understanding into CDKL5 deficiency disease and stimulate new treatments to be developed
Year(s) Of Engagement Activity 2017
 
Description Attendance at the Scottish Parliament - MRC 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Myself, Professor John Rouse and Dr Paul Davies attended an event in the Scottish Parliament on 6th February to support the Medical Research Council's investment in science in Scotland and to present the work that we are doing in the MRC-PPU to MSPs.
Year(s) Of Engagement Activity 2019
 
Description Dolly scientist backs research drive to tackle Parkinson's disease - University of Dundee Press release 
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 Other audiences
Results and Impact Professor Sir Ian Wilmut - who led the team that created Dolly the sheep - has backed an initiative to tackle Parkinson's disease, after being diagnosed with the condition.

The eminent scientist announced his diagnosis today - World Parkinson's Day - ahead of the launch of a major research programme that will see experts at the Universities of Edinburgh and Dundee join forces in the quest to better understand the disease. They will set up infrastructure to enable the first trials in Scotland in a generation for therapies that aim to slow down Parkinson's disease progression.

The new Dundee-Edinburgh Parkinson's Research Initiative aims to probe the causes of disease and translate scientific discoveries into new therapies. The ultimate goal is to find new approaches to predict and prevent Parkinson's, and to facilitate clinical testing of therapies aimed at slowing or reversing disease progression.

Professor Dario Alessi, of the University of Dundee, said, "All attempts to slow the progression of Parkinson's have thus far failed. Surprisingly today's most widely utilised Parkinson's drug levodopa was first used in the clinic in 1967.

"In recent years, our knowledge of the genetics and biology underlining Parkinson's disease has exploded. I feel optimistic and it is not unrealistic that with a coordinated research effort, major strides towards better treating Parkinson's disease can be made."

Parkinson's disease is a progressive condition caused by damage to specific cells in the brain. It affects movement and is often associated with involuntary shaking. Therapies that reduce symptoms can help to prolong quality of life, but currently there are no treatments to slow or halt the progression of the disease.

At present, Scottish patients seeking to take part in clinical trials of treatments that could delay disease progression are required to travel to centres in England or Wales, or even abroad.

Professor Wilmut said, "Initiatives of this kind are very effective not only because they bring more people together, but because they will include people with different experience and expertise. It was from such a rich seedbed that Dolly developed and we can hope for similar benefits in this project."

Dolly the sheep was created at The Roslin Institute in 1996 by a multidisciplinary research team led by Professor Wilmut. She was the first clone of an animal from an adult cell and her birth turned scientific thinking on its head.

It showed that cells from anywhere in the body could be made to behave like a newly fertilised egg - something that scientists had thought was impossible.

This breakthrough paved the way for others to develop a method of using adult cells to produce reprogrammable cells that could develop into any kind of tissue in the body - so called induced pluripotent stem cells, or iPSCs.

These cells hold great promise as therapies because of their potential to repair damaged tissues. The first clinical trials of iPSCs for Parkinson's disease are to begin in Japan later this year.

Dr Tilo Kunath, of Edinburgh's Medical Research Council Centre for Regenerative Medicine, said, "People with Parkinson's urgently require access to earlier and more accurate diagnosis, better prediction of how their disease will progress, and most importantly, the opportunity to participate in clinical trials of new treatments. This new research partnership aims to make these hopes a reality for people in Scotland."

There are more than 12,000 people living with Parkinson's disease in Scotland. Across the UK, the number is expect to double in the next 50 years as the population grows and people live longer.

The Dundee-Edinburgh Parkinson's Research Initiative will be formally launched at a public event at the Royal College of Physicians of Edinburgh on Friday 13 April.
Year(s) Of Engagement Activity 2018
 
Description Dundee Research Interest Group (DRIG) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Myself and several members of my lab, including Dr Esther Sammler and Dr Paul Davies participated in a Parkinson's patients event organised by the Dundee Research Interest Group (DRIG) within the SLS on 18th January 2019.
Year(s) Of Engagement Activity 2019
 
Description Edinburgh Parkinson's seminar that was delivered by Giovanni Mallucci 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact PRC PPU Unit co-sponsored the Edinburgh Parkinson's seminar that was delivered by Giovanni Mallucci in which 300 patients and family members attended. Professor Dario Alessi gave the vote of thanks at the end of the seminar.
Year(s) Of Engagement Activity 2018
 
Description Interview to discuss LRRK2 and Parkinson's Disease 
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 Professional Practitioners
Results and Impact Interview with "Tomorrow Edition" to discuss Parkinson's disease and LRRK2.
Year(s) Of Engagement Activity 2018
URL https://tmrwedition.com/2018/09/18/interview-with-biochemist-and-lrrk2-expert-prof-dario-alessi/
 
Description MRC Festical of Medical Research Inside Out Science Open Day 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact MRC Festival of Medical Research Inside Out Science Open day involved researchers from the MRC Protein Phosphorylation and Ubiquitylation Unit (MRC PPU) and MRC Doctoral Training Programme students (from the Schools of Life Sciences and Medicine at the University of Dundee). The MRC Festival aimed to inform, inspire and stimulate thinking about medical research. Our event was held within the School of Life Sciences and involved seven table top engagement activities, five ten-minute accessible science talks given by PhD students and early career researchers, three lab tours and three videos about the scientific work of the Unit on loop with visitors. There were two new activities called Chromatography and Stem Cell Game trialled that were developed by MRC PPU staff and students plus previously developed activities. Prior to the open day event, a primary six class at Glebelands Primary School attended a 90 minute session to give valuable feedback on talks and new activities.

Members from my lab who participated were;
Elena Purlyte - PhD Student
Alexia Kalogeropoulou - PhD Student
Jordana Freemantle - PhD Student

Overall, 129 members of public (generally family groups) were reached with 103 people visiting on the day, a further 24 Primary Six pupils and their two teachers who gave feedback on the new talks and activities ahead of the event.
The event met a number of the objectives and key messages from the 2018 - 2023 MRC Protein phosphorylation and ubiquitination Public Engagement and Communications Plan which were:

Communications Objectives
1) Generate interest in science as a career path for young people in Dundee to reveal opportunities and make science accessible.
2) Share the unit's research expertise with non-scientific communities to raise awareness of the importance of basic research in understanding health and disease.

Key Messages
1) Basic research is vital - before we can develop new medicines we first need to understand how the body works in health and disease.
2) MRC PPU is an outstanding environment to pursue phosphorylation or ubiquitylation research.
3) As scientists we value new ideas and are open to sharing our work with all who have an interest in it.

Feedback
The visitors to the event were a mixture of ages which included family groups (children under 16 years) and adults up to 70 years of age. Feedback indicated that they enjoyed themselves overall and said they would come to a similar event again. Highlights included a game developed on the topic of Stem Cells and the laboratory tours. Around a third of visitors polled had not attended a University of Dundee event before indicating we were reaching new audiences.
The talks in particular stimulated a number of questions from the audience such as:
• How long does it take for a cell to divide?
• What would happen if you lost all your amino acids?
• Is it only older people who get Parkinson's?
• What is it about not being obese that helps protect you from Alzheimer's?
• What does wildtype mean?

Participants reported having a positive experience, they all said they'd do it again and that they'd recommend a colleague take part too.
Year(s) Of Engagement Activity 2016,2018
 
Description MRC-PPU Collaboration with Baldragon Academy 2014 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The Medical Research Council's Protein Phosphorylation Ubiquitylation Unit (MRCPPU), part of The University of Dundee, has prioritized public engagement in an effort to engage the general public and ensure that the research activities and breakthroughs are communicated to the community. Of equal importance in these communication efforts is educational outreach to students within the Dundee community.

Thus, during session 2014 -2015 and 2015-2016 school year, the MRC-PPU will partner with a local secondary school -- Baldragon Academy (BA). Teachers in BA's Science Department will collaborate with scientists at the MRC-PPU in an educational outreach effort (see Appendix 1). The purpose of this project is to increase interest and engagement in science and related careers. It will be starting in August 2014 with the S1 pupils.

Scientists from the unit will be working with the pupils on a monthly basis at the school during their science classes and will be providing them with opportunities to take part in various science experiments and demonstrations (aligned with Scotland's Curriculum for Excellence). The scientists are leaders in their field of research and as such come from all over the world. They are currently based in Dundee."


Thus far, student have been very enthusiastic about the labs and very receptive to the volunteers. They have asked a multitude of quesitons and have even asked volunteers back to visit.
Year(s) Of Engagement Activity 2014
 
Description MRC-PPU Collaboration with Baldragon Academy 2015 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The Medical Research Council's Protein Phosphorylation Ubiquitylation Unit (MRCPPU), part of The University of Dundee, has prioritized public engagement in an effort to engage the general public and ensure that the research activities and breakthroughs are communicated to the community. Of equal importance in these communication efforts is educational outreach to students within the Dundee community.

Thus, during session 2014 -2015 and 2015-2016 school year, the MRC-PPU will partner with a local secondary school -- Baldragon Academy (BA). Teachers in BA's Science Department will collaborate with scientists at the MRC-PPU in an educational outreach effort (see Appendix 1). The purpose of this project is to increase interest and engagement in science and related careers. It will be starting in August 2014 with the S1 pupils.

Scientists from the unit will be working with the pupils on a monthly basis at the school during their science classes and will be providing them with opportunities to take part in various science experiments and demonstrations (aligned with Scotland's Curriculum for Excellence). The scientists are leaders in their field of research and as such come from all over the world. They are currently based in Dundee.

Thus far, student have been very enthusiastic about the labs and very receptive to the volunteers. They have asked a multitude of questions and have even asked volunteers back to visit. We have also had numerous students of different ages from the school ask to participate in work experience activities to learn more about the Unit and science in general.
Year(s) Of Engagement Activity 2015
 
Description Parkinson's Fundraising Musical Concert - 22/11/15 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact MRC PPU investigators (Drs. Sammler, Muqit and Das) attended on behalf of the Unit. Dr. Sammler spoke about the Unit's research and engaged with patients.

This was a light-hearted musical event whose goal was truly for attendees to enjoy their time, all with the purpose of raising funds for Parkinson's research.
Year(s) Of Engagement Activity 2015
 
Description Parkinson's Open Day 2013 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact As part of the MRC's week of Centenary Celebrations, the MRC-PPU held an Open Day on Parkinson's disease to showcase cutting research being undertaken at the Unit that one day may lead to new treatments for this devastating condition. Highlights included discussions about current targets implicated in PD and the potential for disease modification, as well as an explanation of the the drug development process.


Visitors were very enthusiastic and asked many questions during the talks as well as during the lab tours. As this was the first time for many, they appreciated learning about the breadth of research -- from basic science to therapeutic development -- that is being undertaken at The University of Dundee.
Year(s) Of Engagement Activity 2013
 
Description Parkinson's Open Day 2014 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Given the positive feedback from a previous event, the MRC-PPU held an Open Day on Parkinson's disease to showcase cutting research being undertaken at the Unit that one day may lead to new treatments for this devastating condition. Highlights included discussions about current targets implicated in PD and the potential for disease modification, as well as an explanation of the the drug development process.


Visitors were very enthusiastic and asked many questions during the talks as well as during the lab tours. As this was the first time for many, they appreciated learning about the breadth of research -- from basic science to therapeutic development -- that is being undertaken at The University of Dundee.
Year(s) Of Engagement Activity 2014
 
Description Parkinson's Patient/Parkinson's Uk organised event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Gave a talk on LRRK2 in Parkinson's at a Parkinson's Patient/Parkinson's Uk organised event.
Year(s) Of Engagement Activity 2018
 
Description Parkinson's UK Patient Group Visit - 28/2/15 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Dr. Alessi gave a public engagement talk on Saturday morning (28th Feb 2015) to a group of ~30 Parkinson's patients and their families. This is the Edinburgh Branch of Parkinson's UK and the group called the ERIG (Edinburgh Research Interest Group).

Professor Alessi gave an hour talk on the importance of research in Parkinson's disease emphasising what your Unit was doing and why he thought that this was very important. The talk lasted about an hour and he spent about 90 min talking to the members of the group. The talk was held at the SCRM building at the University of Edinburgh Little France. Patients asked numerous questions about the current state of disease modifying treatments for Parkinson's disease
Year(s) Of Engagement Activity 2015
 
Description Parkinson's UK Supporters Event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Discussing mine and the units research and projects to Parkinson's supporters at the Parkinson's UK Supporters Event on 2nd July 2018
Year(s) Of Engagement Activity 2018
 
Description Radio interview with Tay fm 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact Conducted a Radio interview with local station Tay FM to discuss the recent press release by University of Dundee, titled "Dolly scientist backs research drive to tackle Parkinson's disease"
Year(s) Of Engagement Activity 2018
 
Description Visit from Annie MacLeod, Scotland Director for Parkinson's UKs 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Industry/Business
Results and Impact Annie MacLeod, Scotland Director for Parkinson's UK visit our lab on Thursday 7th March. The purpose of Annie's visit was to find out more about our research. Annie also had a tour of our labs as well as meeting with myself, Miratul Muqit and Esther Sammler.
Year(s) Of Engagement Activity 2019