Understanding Signalling Pathways Mutated in Inherited Disorders

Lead Research Organisation: University of Dundee

Abstract

My laboratory focuses on unravelling the roles played by an important class of enzymes that are implicated in human disease, that control a biological process known as “protein phosphorylation”. Many diseases including Parkinson’s disease, cancer and high blood pressure, are caused by alterations in specific pathways that regulate protein phosphorylation. My research programme will be based on deciphering the molecular details of protein phosphorylation pathways that are associated with Parkinson’s Disease (LRRK2), cancer (SGK3 pathway) and hypertension (WNK pathway). The overarching goal of our research is to discover how disruptions in enzymes that regulate phosphorylation are linked to human disease. We aim to harness this information and work with clinicians as well as pharmaceutical companies to develop improved strategies to better treat and diagnose malady.

Technical Summary

My laboratory focuses on unravelling the roles played by protein phosphorylation and ubiquitylation pathway components that emerge from the genetic analysis of human disease. In the current quinquennium the attention will be based on dissecting signalling pathways associated with Parkinson’s Disease (LRRK2), cancer (SGK3 pathway) and hypertension (WNK pathway). The aim of our research is to focus om mechanism and understand how the signalling components that we are studying are regulated and function. How mutations in these pathways disrupts biology to cause disease is also a major question. We hope to harness this information to elaborate a better understanding of human disease and to develop improved strategies to better treat and diagnose malady. For the LRRK2 research the key aims of this work are: 1. Do mutations in “Parkinson’s genes” promote LRRK2 activity and Rab protein phosphorylation? 2. Are there any specific stimuli that induce activation of LRRK2 and phosphorylation of Rab proteins? 3. How does LRRK2 mediated phosphorylation of Rab GTPases affect downstream biology? 4. Generation and use of monoclonal antibodies to better detect endogenous phosphorylation of Rab proteins by LRRK2. In parallel to this research we are working with clinicians and pharmaceutical companies with an interest in testing the therapeutic benefit of LRRK2 inhibitors for the treatment of Parkinson’s. For the SGK3 project the work will focus on studying the regulation and function of SGK3 in caner. The aims are: 1. Obtain a better understanding SGK3 biology-identification of novel SGK3 substrates in breast cancer cells; 2. How is SGK3 activated by Growth Factors. This work will help define whether SGK3 inhibitors will have therapeutic benefit for cancer. The WNK project concerns understanding how the WNK kinases that control blood pressure are regulated. This project could provide fundamental information of how cells sense and respond to osmotic and ionic stress, cellular processes that are very poorly understood.

Publications

10 25 50
 
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 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 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 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 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 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 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 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 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