The Molecular Basis of Gating & High Affinity Drug Block of HERG Potassium Channels Associated with Cardiac Arrhythmia

Lead Research Organisation: University of Leicester
Department Name: Cell Physiology and Pharmacology

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Publications

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Stansfeld PJ (2006) Molecular mechanisms for drug interactions with hERG that cause long QT syndrome. in Expert opinion on drug metabolism & toxicology

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Kamiya K (2006) Molecular determinants of HERG channel block. in Molecular pharmacology

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Cockerill SL (2006) Direct block of human ether-a-go-go-related gene potassium channels by caffeine. in The Journal of pharmacology and experimental therapeutics

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Mitcheson JS (2008) hERG potassium channels and the structural basis of drug-induced arrhythmias. in Chemical research in toxicology

 
Description BHF Project Grant
Amount £146,188 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2006 
End 08/2008
 
Description Novartis MRCCASE PhD Studentship
Amount £70,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2007 
End 09/2011
 
Description Novartis/MRC CASE PhD studentship
Amount £70,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2003 
End 09/2006
 
Title In-silico model of hERG potassium channel 
Description Developed and improved in-silico models of hERG potassium channels for investigating drug induced long QT syndrome 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2007 
Provided To Others? Yes  
Impact Significantly enhanced our understanding of drug-induced long QT syndrome. Also very useful tool for developing new hypotheses. Used by pharmaceutical companies in drug development 
 
Title molecular biology reagents 
Description Generated plasmid constructs and hERG and hEAG channel mutants 
Type Of Material Technology assay or reagent 
Year Produced 2006 
Provided To Others? Yes  
Impact Used as research materials by several collaborators 
 
Description A chimeric approach to investigating drug binding in HERG channels. 
Organisation Novartis
Country Global 
Sector Private 
PI Contribution We have provided expertise and experimental know-how that has guided their research
Collaborator Contribution They have provided resources and access to equipment that have facilitated our research
Impact The collaboration resulted in a student gaining his PhD. There are publications in the pipeline. Further funding support from Novartis also resulted from this collaboration.
 
Description Astrazeneca collaboration 
Organisation AstraZeneca
Department Drug Safety and Metabolism Externalisation
Country United Kingdom 
Sector Private 
PI Contribution We provided training in experimental techniques. We guided the direction of the project and the experimental design
Collaborator Contribution Provided funding, reagents, infrastructure, and day to day supervision of Postdoctoral research assistant
Impact This collaboration enabled our collaborators to establish assays and knowhow that have been valuable in their research. The collaboration resulted in a publication 15574182
 
Description Collaboration with Prof Recanatini 
Organisation University of Bologna
Department Department of Pharmacy and Biotechnology (FaBiT)
Country Italy 
Sector Academic/University 
PI Contribution Provided technical expertise and performed electrophysiology experiments. Has resulted in a publication. 22455383
Collaborator Contribution Performed computational modelling and analysis
Impact 22455383
Start Year 2008
 
Description EPIX contract research 
Organisation Epix Pharmaceuticals
Country United States 
Sector Private 
PI Contribution We investigated the drug interactions with ion channels
Collaborator Contribution Provided funding and compounds to be tested
Impact It provided research income to fund other basic science projects and equipment for the lab. Outcomes are subject to confidentiality agreements
Start Year 2007
 
Description HERG channel gating and pharmacology. 
Organisation Pfizer Ltd
Country United Kingdom 
Sector Private 
PI Contribution We have provided expertise and experimental know-how that has guided their research
Collaborator Contribution They gave us access to automated patch clamp equipment and consumables that enabled us to do experiments that would otherwise have been unfeasible.
Impact The collaboration resulted in a student gaining her PhD. One manuscript with support from this collaboration has been published - 17823114. Two other publications are in the pipeline.
 
Description hERG potassium channel pharmacology 
Organisation AstraZeneca
Country United Kingdom 
Sector Private 
PI Contribution We provided training in experimental techniques. We guided the direction of the project and the experimental design
Collaborator Contribution Provides additional resources for research and discussions have been useful for guiding current and potential future projects
Impact This collaboration enabled our collaborators to establish assays and know-how that have been valuable in their research. The collaboration resulted in a publication - 15574182
 
Description Invited seminars at academic institutions 
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 One hour seminars followed by discussions with primary investigators at academic institutions

Helped with setting up of collaborations
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015
 
Description Symposium presentations 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact I have given several research presentations to mixed audiences of academics and industry scientists

Helped with the setting up of collaborations
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description UCAS day demonstrations 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact Groups of 20+ school pupils attend demonstrations and workshops of physiology experiments. Engaged children in subject of physiology and encouraged them to consider scientific career.

Engaged pupils and encouraged them to do University degree.
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012
 
Description University Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public open days. Run practical demonstrations for public on the electrocardiogram, vitalographs and other physiological functions. Discussed research with interested members of the public

Generated considerable interest in local community
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018,2019
 
Description Work experience for school pupils 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact A-level pupils spend time in my laboratory and find out more about scientific research and careers

Pupils motivated to go to University and consider research careers
Year(s) Of Engagement Activity 2008,2010,2012