Molecular regulation of autophagy in health and disease

Lead Research Organisation: University of Dundee

Abstract

The cells of our body are constantly exposed to potentially damaging agents from both external sources, such as the sun's harmful UV rays or pathogenic bacteria, as well as internal sources, including free radicals produced by the cell’s metabolic pathways. A key mechanism that helps us cope with this onslaught is autophagy (which literally means self eating) whereby damaged and unwanted cellular components are targeted for degradation and recycling. Recent work has indicated that impaired autophagy is linked to many diseases such as cancer, Parkinsons and tuberculosis, therefore any drug that could target this process might be advantageous in treating these diseases. The actual mechanism of autophagy remains elusive and the aim of my lab is to understand how autophagy is regulated and proceeds at the molecular level. We also aim to unravel how the disruption of autophagic pathways can lead to disease and to exploit this information to develop novel therapeutic strategies.

Technical Summary

A major focus of this research is to decipher the signals that initiate autophagy and determine how these signals trigger autophagosome formation. Autophagy is a conserved catabolic process for degrading unwanted, damaged or foreign components in eukaryotic cells. Autophagy is critical for various physiological processes such as embryonic development and establishment of self-tolerance in the immune system. Additionally, malfunction of autophagy is involved in multiple human diseases including cancer, Parkinsons and Crohns. Autophagy occurs when a small membrane cistern grows and surrounds a portion of the cytosol, eventually sealing itself to form a double-membrane vesicular structure termed an autophagosome. The outer membrane of the autophagosome then fuses with the endocytic system to deliver the internal membrane and its contents to the lysosome for degradation and recycling. Under conditions of stress, such as nutrient starvation or infection, autophagy is strongly induced, yet the signaling pathways that lead to this increase in autophagic flux are poorly understood. We recently identified a protein kinase complex that is essential for the early stages of autophagy. The complex consists of at least three proteins: the kinase ULK1 and its accessory proteins ATG13 and FIP200. Importantly, it appears that this complex acts as a signaling node to convert incoming autophagy signals into autophagosomes. We aim to identify the signaling pathways that initiate autophagy with stimuli including nutrient starvation, ER stress and innate immune responses. Using biochemical and cell biological techniques we will define how these pathways interact with the ULK1 complex and in-turn how ULK1 kinase activity is altered. Importantly, we will use this information to determine the downstream targets of ULK1 to understand how autophagy is induced. Another related focus of the lab is to determine how autophagy can target specific cellular components in the background of all others. Traditionally autophagy was seen as a non-specific pathway, with random portions of the cytosol targeted for degradation. However, recent work has shown that autophagy can target specific proteins and organelles within the cell. For example, specific targets include mitochondria, which has implications for the neurodegenerative Parkinson's disease, and intracellular pathogens such as Mycobacterium tuberculosis. As with proteasomal-mediated degradation, ubiquitylation appears to be the signal for autophagic turnover. We are interested in how this ubiquitylation signals to the autophagic machinery, specifically the ULK1 complex, to trigger the switch from a general, non-specific autophagy into a targeted, specific autophagy.

Publications

10 25 50
 
Description Priority Target Award Fall 2015 Program
Amount $97,924 (USD)
Funding ID 11470 
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 03/2016 
End 03/2017
 
Description Priority Target Award Program
Amount $285,929 (USD)
Funding ID 11470.01 
Organisation Michael J Fox Foundation 
Sector Charity/Non Profit
Country United States
Start 11/2017 
End 11/2020
 
Title Mitophagy Reporter 
Description cDNA expression construct that allows the specific monitoring of mitophagy (degradation of mitochondria in lysosomes) in mammalian cells. 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact Increased recognition of my work Increased collaborations 
URL http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981094/
 
Title mito-QC 
Description We have developed a reporter mouse that allows the monitoring of mitochondrial architecture and mitochondrial delivery to lysosomes (mitophagy) in tissues. Mitophagy has been linked to many diseases, including Parkinson's, and it is hoped this model will greatly help in understanding how these diseases progress and how they might be treated. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2016 
Provided To Others? Yes  
Impact This has increased my collaborations and there is interest from pharmaceutical companies. 
URL http://jcb.rupress.org/content/214/3/333.long
 
Description Andrew P 
Organisation The Garvan Institute for Medical Research
Department Diabetes and Metabolism
Country Australia 
Sector Hospitals 
PI Contribution We are supplying reagents and expertise.
Collaborator Contribution We will gain information of the role of exercise and muscle mitophagy
Impact .
Start Year 2016
 
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 Inc
Country United States 
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 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.
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 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.
Start Year 2016
 
Description DSTT renewal 2016 
Organisation Merck
Department Merck Serono
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 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.
Start Year 2016
 
Description Jo P 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution We are supplying reagents and expertise.
Collaborator Contribution We will gain knowledge on the potential of mitophagy for disease treatment.
Impact .
Start Year 2016
 
Description Role of autophagy in chronic lymphocytic leukemia (CLL) 
Organisation University of Dundee
Department College of Medicine, Dentistry & Nursing
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided expert advice, reagents and data analysis.
Collaborator Contribution Brought about a new, medically relevant, system in which to study signalling pathways involved in autophagy regulation.
Impact Two manuscripts have been published so far (PMID:24091621 and 23429453)
Start Year 2010
 
Description Role of coibamide-induced autophagy 
Organisation Oregon State University
Department Department of Pharmaceutical Sciences
Country United States 
Sector Academic/University 
PI Contribution Provided expertise and reagents to monitor autophagy. Paper published (PMID: 23762328).
Collaborator Contribution Identified a natural product, coibamide, that induces autophagy and kills cancer cells.
Impact Pharmacology, biochemistry and cell biology. Two papers published (PMID: 23762328 and 29494533).
Start Year 2011
 
Description Simon B 
Organisation Cardiff University
Department School of Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution We are undertaking experimental work and contributing expertise and intellectual input.
Collaborator Contribution They are providing expertise in lesion studies.
Impact Two Publications: 1: McWilliams TG, Barini E, Pohjolan-Pirhonen R, Brooks SP, Singh F, Burel S, Balk K, Kumar A, Montava-Garriga L, Prescott AR, Hassoun SM, Mouton-Liger F, Ball G, Hills R, Knebel A, Ulusoy A, Di Monte DA, Tamjar J, Antico O, Fears K, Smith L, Brambilla R, Palin E, Valori M, Eerola-Rautio J, Tienari P, Corti O, Dunnett SB, Ganley IG, Suomalainen A, Muqit MMK. Phosphorylation of Parkin at serine 65 is essential for its activation in vivo. Open Biol. 2018 Nov 7;8(11). PubMed PMID: 30404819. 2: McWilliams TG, Prescott AR, Montava-Garriga L, Ball G, Singh F, Barini E, Muqit MMK, Brooks SP, Ganley IG. Basal Mitophagy Occurs Independently of PINK1 in Mouse Tissues of High Metabolic Demand. Cell Metab. 2018 Feb 6;27(2):439-449. PubMed PMID: 29337137.
Start Year 2016
 
Description Steve J 
Organisation University of Cambridge
Department Gurdon Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are undertaking experimental work and contributing expertise and intellectual input.
Collaborator Contribution Collaborators are undertaking experimental work and contributing expertise and intellectual input..
Impact .
Start Year 2016
 
Description Tobias H 
Organisation Harvard University
Department Renal Division
Country United States 
Sector Academic/University 
PI Contribution We are supplying reagents and expertise to collaboration.
Collaborator Contribution The collaboration will provide useful physiological information for us.
Impact .
Start Year 2016
 
Description Art & Science Collaboration 
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 Postgraduate students
Results and Impact In an effort to try public engagement in a different way, the PPU will be inviting some artists shortly. As a reminder, we'll be having 6 artists from the Medical Science Illustrators course at The Duncan and Jordanstone College of Art & Design visited The MRC Protein Phosphorylation and Ubiquitylation Unit.

The goal of this effort was a few-fold:
1. To identify points in investigators' own research that might be conveyed in a different way to the general public as well as an artist who can assist them;
2. To identify a project for the artists who may wish to learn more about the science going on so close to home
3. To create a final piece which (ideally) may become part of an installation in the Discovery Centre at The University of Dundee to convey science to new audiences
Year(s) Of Engagement Activity 2015
 
Description Debating Matters Judge 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Member of a three judge panel in the Scotland and Northern Ireland Regional finals and qualifying rounds of the national Debating Matters competition. Challenged debaters (6th form levels students) with questions and provided critique following debate on science-based topics

Following the debates, a number of students were thinking about a science-based career and were interested in my thoughts and how to go about it.
Year(s) Of Engagement Activity 2013
URL http://www.debatingmatters.com/
 
Description Dundee Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The interactive games will incorporate knowledge and engage children to ultimately convey fundamental science, teach them about cells, disease and how therapies are achieved. Each is a research effort currently being pursued by those who will be involved with the event. Thus, this event brings together a number of experts from the MRC Protein Phosphorylation Unit from all levels - student, staff and postdoctoral fellows. In this way, we hope to highlight some of the cutting edge science that is ongoing here in Dundee and provide a venue for adults and children to ask questions from scientists firsthand.

Students and children were encouraged to learn about the cells and how sometimes bad things happen to good cells. They participated in activities and games that ultimately conveyed the impact of the ongoing research at the MRC PPU plays a role in better understanding this disease and developing better therapeutics to combat it.
Year(s) Of Engagement Activity 2014
URL http://www.dundeesciencecentre.org.uk/contents/dundee_science_festival.html
 
Description Edinburgh Science Festival Outreach 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Each activity in included in Mini Scientists is designed to be fun and to teach some basic principles about science and research. Scientists from all of the MRC units and centres in Scotland took the opportunity to take part as demonstrators and boost their science communication skills.

Many children attended and learned about MRC research as well as basic building blocks pertinent to our research.
Year(s) Of Engagement Activity 2014
URL http://www.insight.mrc.ac.uk/tag/edinburgh-international-science-festival/
 
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 Open Days at University of Dundee 
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 Public/other audiences
Results and Impact People, young and old, were exposed to the research activities at the University of Dundee.

A number of people were very interested in our research and requested further information about cancer.
Year(s) Of Engagement Activity 2015
 
Description Science-Art Tutor 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Tutor in a course aimed at 3rd year art students who wish to develop an interest in the relationship between art and science. My role has involved describing aspects of my work to an audience of ~20 art students. The course is still running and it is the hope that collaborations will develop to produce an art piece, based on science, that will be displayed to the general public.

Course is still on-going. It is the hope that an art piece will be produced that will further the interest of the general public into the science behind the art.
Year(s) Of Engagement Activity 2012,2013,2014
 
Description Scientific Lead on Animating Science 
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 Animating Science is an exciting pilot project under the banner of STEAM (taking STEM and adding A for arts). University of Dundee's School of Life Sciences has partnered with Dundee Contemporary Arts Learning to deliver a unique art and science collaborative programme supported by Wellcome through the Institutional Strategic Support Fund.
Animating Science aims to develop stop motion animation skills with pupils and teachers (P7 - S3) and support them in creating animated films about Life Science concepts and processes. This will deepen pupils' engagement and science understanding and make science learning more fun.
Researchers contributed guidance on a science topic chosen by participating classes, including a lesson with hands-on activities and experiments. They then re-visited the class during the writing and filming of the project to advise on the story and script to ensure it was scientifically accurate. At the end of the project they attended a 'film premiere' where the finished product was shown to the entire school as well as parents and teachers.
Significant impact (drop down box)
• Audience reported change in views, opinions or behaviour
• Own/colleagues reported change in views or opinions
• Decision made or influences
Pupils taking part reported increased confidence engaging in science as well as increased fluency in scientific vocabulary. Teacher observation reported excellent levels of team working and engagement from pupils who are traditionally more disruptive or unengaged with regular classwork.
"[I learned] to co-operate, pay attention, animate and play with it. It helped me be creative."
As a result of taking part in this project the concept of using animation to cement science learning has been adapted as part of an undergraduate module.
Year(s) Of Engagement Activity 2016,2017,2018,2019,2020
URL http://www.lifesci.dundee.ac.uk/impact/schools-outreach/animating-science-workshops
 
Description Understanding Cancer Day 
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 Public/other audiences
Results and Impact Our objective with this event was to communicate our research to members of the public. We advertised our event through local cancer patient groups and cancer charities. 40 visitors attended including cancer survivors, current cancer patients, relatives of cancer patients, cancer charity workers and school children.

The day started with a general introduction to our unit and cancer research in our unit from Prof John Rouse. Prof Rouse, Dr Victoria Cowling and Dr Ian Ganley then explained their current research questions. This session was directly followed by a lively question and answer session, including discussion of our research and cancer research in general. During a refreshment break there was opportunity for more informal discussions with the Prof Rouse, Dr Cowling and Dr Ganley. At this time, lab tours were also conducted including demonstrating mass spectrometry, live cell imaging and the MRC-PPU research area. Dr Matthias Trost, Dr Thimo Kurz and Dr Yogesh Kaluthu assisted with the tours. A number of postdocs and PhD students were also involved throughout the day.

10 MRC staff took part in the day.
4 invitations were issued: 3 cancer patient groups and 1 cancer charity
40 visitors attended


Feedback from the visitors was positive.
100% of guests "completely enjoyed the event.
There was equivalent interest in:
- learning more about cancer research
- meeting and chatting to scientists
- finding out how medical research affects health
100% wanted to attend a similar event in the future.
Year(s) Of Engagement Activity 2013
 
Description Work Experience Student Visit 
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 Schools
Results and Impact The goal of this work experience is to provide secondary school students with an interest in biological sciences with several 'taster sessions' focused on diverse laboratory training focused on specific topics carried out in the PPU -- which are also critical parts of molecular and cellular biochemisty.

A young S5 student visited with 6 different labs to better understand techniques ranging from plasmid and protein generation to cell culture and animal dissection.
Year(s) Of Engagement Activity 2014