The molecular function of the Popeye domain containing genes in the heart
Lead Research Organisation:
Imperial College London
Department Name: National Heart and Lung Institute
Abstract
The electrical impulse, which stimulates the beating of our heart, is generated in an oscillatory fashion in a small cluster of cardiac cells, which is called the sinuatrial node. The node cells will pace the heart at different frequencies, depending on the physiological demands. An increase in beating frequency is mediated by the release of adrenergic hormones, which stimulates pacemaker activity in sinuatrial node cells. We have identified a gene family called the Popeye domain containing genes, which have an important but not yet fully understood role in regulating pacemaker activity. We have observed in mouse models lacking single Popdc genes an inability of the sinuatrial node to adapt to physical activity. Hearts of these mutant animals were unable to increase heart frequency in response to stress, but rather the stressed heart was beating at a lower frequency or was not beating at all for short periods of time. Mutations in one member of this gene family were also identified in patients with abnormally slow heart frequency, strongly suggesting that these proteins are an essential component for proper functioning of the cardiac pacemaker. In this grant proposal we will perform further genetic experiments in mice to fully understand the role of the different family members in cardiac pacemaker function. Moreover the precise mechanisms by which these proteins are accomplishing their tasks within sinuatrial node cells will be further analyzed by making specific mutations in essential parts of the protein. We will also generate a mouse model for the human point mutation in order to further learn how these molecular alterations affect cardiac pacemaking and analyze the biophysical and biochemical mechanisms by which the Popeye domain containing proteins stimulate pacemaker activity in sinuatrial node cells. We are convinced that the proposed experiments will help to define the role of this gene family in the heart, which is vital to our survival and wellbeing.
Technical Summary
The Popeye domain containing (Popdc) genes are involved in adrenergic signaling in the heart. In order to overcome genetic redundancy, mice will be generated that lack the entire gene family and will be phenotypically assessed by ECG analysis. In order to assess the phenotypic consequences, a point mutation will be introduced into mice, which interferes with cAMP binding, and a nonsense mutation, which is present in patients with severe early onset bradycardia. In order to identify ion channels with which Popdc proteins might interact, we will analyze the action potentials of cardiac myocytes isolated from different null mutants. Alterations in ion channel anatomy might lead to the identification of malfunctioning currents and ultimately to ion channels, which directly interact with Popdc proteins. Candidates will be further assessed by co-localization and immunoprecipitation analysis. This study is likely to provide novel opportunities for rational drug design.
Planned Impact
Impact Summary
This grant proposal aims at defining the function of the Popeye domain containing genes. The nature of this grant application is to perform basic research, which will therefore be primarily of interest to other academic researchers worldwide, which are interested in the membrane biology of cardiac myocytes, in cyclic AMP binding proteins, or working on cardiac pacemaker function. With this research we will provide novel insight into cardiac pacemaker function, which is a scientific area that still lacks a complete understanding of how the cardiac pacemaker works and in particular how adrenergic signaling might have its impact on cardiac pacemaking. The animal models that we have already generated and will be generating during the course of this grant might be of interest to research labs interested in developing biological pacemakers, since we have observed gradual loss of pacemaker cells in the null mutant animals. Since we have identified Popdc proteins as novel cAMP binding proteins we feel that, in the longer term , these proteins might also become a target for drug development in order to modulate cardiac pacemaker function. The mouse models might also be of use to study therapeutic interventions to prevent the development of sick sinus syndrome, a condition which develops in the elderly patient and for which currently the only therapeutic option is the implantation of a pacemaker devices. Since a significant fraction of the total pacemaker implants are due to sinus dysfunction, the development of novel options for therapeutic intervention would result in a significant cost reduction for the health sector. However, this will require further research into this subject beyond the current grant application. The mice will however also be further exploited by collaborating with labs interested in organ systems which also show strong and specific gene expression of Popdc genes, but which are outside the primary interest of the applicants. The use of tissue-specific Cre lines will allow the assessment of organ-specific functions of the Popdc genes. In this regard the recent observation that Popdc genes are associated with the development of colon cancer is an example of possible future collaborations. We are also proposing to generate an animal model for a human mutation we have found in one of the Popdc genes in patients having a severe and early onset bradycardia. We are particularly interested in studying the phenotype of this mutant and whether this acts as a dominant negative mutation but this research most likely will foster further search into mutations in Popdc genes associated with various forms of cardiac arrhythmia.
This grant proposal aims at defining the function of the Popeye domain containing genes. The nature of this grant application is to perform basic research, which will therefore be primarily of interest to other academic researchers worldwide, which are interested in the membrane biology of cardiac myocytes, in cyclic AMP binding proteins, or working on cardiac pacemaker function. With this research we will provide novel insight into cardiac pacemaker function, which is a scientific area that still lacks a complete understanding of how the cardiac pacemaker works and in particular how adrenergic signaling might have its impact on cardiac pacemaking. The animal models that we have already generated and will be generating during the course of this grant might be of interest to research labs interested in developing biological pacemakers, since we have observed gradual loss of pacemaker cells in the null mutant animals. Since we have identified Popdc proteins as novel cAMP binding proteins we feel that, in the longer term , these proteins might also become a target for drug development in order to modulate cardiac pacemaker function. The mouse models might also be of use to study therapeutic interventions to prevent the development of sick sinus syndrome, a condition which develops in the elderly patient and for which currently the only therapeutic option is the implantation of a pacemaker devices. Since a significant fraction of the total pacemaker implants are due to sinus dysfunction, the development of novel options for therapeutic intervention would result in a significant cost reduction for the health sector. However, this will require further research into this subject beyond the current grant application. The mice will however also be further exploited by collaborating with labs interested in organ systems which also show strong and specific gene expression of Popdc genes, but which are outside the primary interest of the applicants. The use of tissue-specific Cre lines will allow the assessment of organ-specific functions of the Popdc genes. In this regard the recent observation that Popdc genes are associated with the development of colon cancer is an example of possible future collaborations. We are also proposing to generate an animal model for a human mutation we have found in one of the Popdc genes in patients having a severe and early onset bradycardia. We are particularly interested in studying the phenotype of this mutant and whether this acts as a dominant negative mutation but this research most likely will foster further search into mutations in Popdc genes associated with various forms of cardiac arrhythmia.
Organisations
- Imperial College London (Lead Research Organisation)
- Philipp University of Marburg (Collaboration)
- University of Innsbruck (Collaboration)
- University of Kassel (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- Max Planck Society (Collaboration)
- Ohio State University (Collaboration)
- UNIVERSITY OF BIRMINGHAM (Collaboration)
- BioLog (Collaboration)
- Research Complex at Harwell (Collaboration)
- University of Iowa (Collaboration)
- Pierre and Marie Curie University - Paris 6 (Collaboration)
- University of Ferrara (Collaboration)
- University of Manchester (Collaboration)
- University of Copenhagen (Collaboration)
- University of Mons (Collaboration)
- Oswestry Hospital (Collaboration)
- Newcastle University (Collaboration)
- University of Montpellier (Collaboration)
- Dalhousie University (Collaboration)
- The University of Texas at San Antonio (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
- Heart and Diabetes Centre North Rhine-Westphalia (HDZ NRW) (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- UNIVERSITY OF GLASGOW (Collaboration)
- KING'S COLLEGE LONDON (Collaboration)
Publications
Schindler RF
(2016)
POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking.
in The Journal of clinical investigation
Shetty M
(2022)
Mice lacking the cAMP effector protein POPDC1 show enhanced hippocampal synaptic plasticity
in Cerebral Cortex
Simrick S
(2013)
Popeye domain-containing proteins and stress-mediated modulation of cardiac pacemaking.
in Trends in cardiovascular medicine
Description | Confidence in Concept |
Amount | £59,500 (GBP) |
Funding ID | P56982 |
Organisation | Imperial College London |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2015 |
End | 07/2016 |
Description | Disease modelling of the POPDC1S201F and the POPDC2W188X mutations associated with cardiac arrhythmia |
Amount | £297,638 (GBP) |
Funding ID | 191334247 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2019 |
End | 04/2022 |
Description | ICB-CDT British Heart Foundation |
Amount | £70,000 (GBP) |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2017 |
End | 09/2021 |
Description | ICTEM BHF MRes/PhD 4-year Studentship |
Amount | £638,824 (GBP) |
Funding ID | 66590_WHCF |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2016 |
End | 09/2020 |
Description | Non-Clinical PhD Studentship |
Amount | £120,172 (GBP) |
Funding ID | FS/17/10/32677 |
Organisation | British Heart Foundation (BHF) |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2017 |
End | 04/2020 |
Description | Research Project |
Amount | € 45,000 (EUR) |
Funding ID | 19469 |
Organisation | French Muscular Dystrophy Association (AFM) |
Sector | Charity/Non Profit |
Country | France |
Start | 06/2016 |
End | 06/2018 |
Title | Conditional Popdc1 mutant |
Description | A knockin mutant of Popdc1 was engineered in order to make null mutants in a conditional and tissue specific way. |
Type Of Material | Biological samples |
Provided To Others? | No |
Impact | Not yet |
Title | Popdc2 KI D184A |
Description | This mutation renders the mutant Popdc2 protein unable to bind cAMP. The importance of cAMP binding for the biological function of Popdc2 will be studied. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | Will establish the role of cAMP binding for the biological function of Popdc2 protein. |
Title | Popdc2 KI of a W188X mutation |
Description | A mouse model of a human mutation associated with cardiac arrhythmia in patients. |
Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
Provided To Others? | No |
Impact | It will be possible to study the molecular basis of the observed pathologies in patients |
Title | Popdc3-R261Q |
Description | A KI mutant established by CRISPR-Cas9 to model a mutation found in patients |
Type Of Material | Model of mechanisms or symptoms - non-mammalian in vivo |
Year Produced | 2019 |
Provided To Others? | No |
Impact | Possibility to establish disease mechansism |
Description | Ankyrin Interaction |
Organisation | Ohio State University |
Department | Dorothy M Davis Heart and Lung Research Institute |
Country | United States |
Sector | Academic/University |
PI Contribution | Collaborative Research on the role of Ankyrins as mediators of Popdc function |
Collaborator Contribution | Provides knockout lines, cells tissues to study the importance of Ankyrins in mediating interactions with other proteins such as the sodium channel, the sodium calcium exchanger, dystrophin, the sodium potassium exchanger |
Impact | publications are planned |
Start Year | 2013 |
Description | Arrhythmia |
Organisation | University of Birmingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Generating mouse mutants for Popdc genes. Heart rhythm analysis after stress induction. |
Collaborator Contribution | Analysis of cardiac arrhythmia data. Help with proper clinical assignment of cardiac arrhythmias. |
Impact | We have already published a paper together in the Journal of Clinical Investigation in 2012. We will publish another paper together in the near future. |
Start Year | 2006 |
Description | Calcium and cardiac pacemaking |
Organisation | University of Montpellier |
Country | France |
Sector | Academic/University |
PI Contribution | Expertise and mouse model |
Collaborator Contribution | Expertise in Calcium signalling in cardiac pacemaking |
Impact | not yet |
Start Year | 2016 |
Description | Hippocampus |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We probed hippocampal synaptosome extracts by Western blot for expression of Popdc1 protein. |
Collaborator Contribution | Provided hippocampal synaptosome preparation |
Impact | We are in the process of submitting a grant application to study memory formation in Popdc mutants. |
Start Year | 2013 |
Description | Human genetics |
Organisation | Heart and Diabetes Centre North Rhine-Westphalia (HDZ NRW) |
Country | Germany |
Sector | Hospitals |
PI Contribution | Characterisation of a mutation in POPDC1 |
Collaborator Contribution | Identification of POPDC1 mutation, which is associated with Heart Failure |
Impact | We are currently in the process of submitting a manuscript. Recently an abstract has been sent. |
Start Year | 2012 |
Description | Ion scanning conductance |
Organisation | Imperial College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are generating mouse mutants of the Popdc gene family. |
Collaborator Contribution | They are able to perform ion scanning conductance microscopy combined with patch clamp analysis, which allows to to map ion channel distribution and function in relation to plasma membrane topography. Since our preliminary data suggests that the cardiac arrhythmia phenotype observed in animal models having mutations in Popdc1 is due to alterations membrane trafficking and cluster formation, we are optimistic that with high resolution analysis we will obtain further evidence for this phenotype. |
Impact | no outputs yet |
Start Year | 2013 |
Description | Memory |
Organisation | University of Mons |
Country | Belgium |
Sector | Academic/University |
PI Contribution | We generated Popdc1 mouse mutants |
Collaborator Contribution | Measurement of LTP in hippocampal slices of Popdc1 mutants. These experiments established that Popdc1 has a functional role in memory formation. |
Impact | We have generated preliminary data suggesting that Popdc1 has a role in memory formation mediating adrenergic signalling/cAMP signalling in hippocampal CA1 neutrons, suggesting that the mechanisms we are currently observing in the heart possibly also applying to the hippocampus, i.e. Popdc1 interacts via Ankyrin G with ion channel controlling their clustering and trafficking. Grant application is underway. |
Start Year | 2013 |
Description | Molecular Mechanism of Memory Formation |
Organisation | University of Iowa |
Department | Department of Otolaryngology |
Country | United States |
Sector | Academic/University |
PI Contribution | Popdc1, Popdc3 and Popdc1?Popdc3 null mouse mutants |
Collaborator Contribution | Expertise in Learning Tests and Molecular basis of memory formation. |
Impact | not yet |
Start Year | 2016 |
Description | Monoclonal antibodies |
Organisation | Oswestry Hospital |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | Recombinant Popdc proteins produced |
Collaborator Contribution | Genration of Monoclonal antibodies |
Impact | Nothing yet to report. Production of antibodies has just started |
Start Year | 2015 |
Description | Monoclonal antibodies |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Recombinant Popdc proteins produced |
Collaborator Contribution | Genration of Monoclonal antibodies |
Impact | Nothing yet to report. Production of antibodies has just started |
Start Year | 2015 |
Description | Muscle Genetics |
Organisation | University of Ferrara |
Country | Italy |
Sector | Academic/University |
PI Contribution | We are analysing the cell biology and biochemistry of POPDC1 mutations found in patients with cardiac arrhythmia and muscular dystrophy. |
Collaborator Contribution | Identification of human mutations in POPDC1 |
Impact | Schindler RF, Scotton C, French V, Ferlini A, Brand T (2016). The Popeye Domain Containing Genes and their Function in Striated Muscle. J Cardiovasc Dev Dis. 3:22. Schindler RF, Scotton C, Zhang J, Passarelli C, Ortiz-Bonnin B, Simrick S, Schwerte T, Poon KL, Fang M, Rinné S, Froese A, Nikolaev VO, Grunert C, Müller T, Tasca G, Sarathchandra P, Drago F, Dallapiccola B, Rapezzi C, Arbustini E, Di Raimo FR, Neri M, Selvatici R, Gualandi F, Fattori F, Pietrangelo A, Li W, Jiang H, Xu X, Bertini E, Decher N, Wang J, Brand T, Ferlini A (2016 ). POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. J Clin Invest.126:239-53. |
Start Year | 2012 |
Description | Nuclear Envelope |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in the Popeye domain containing genes |
Collaborator Contribution | Expertise in Nuclear Envelope Protein Biochemistry |
Impact | not yet. Attempts to get funding for the work hasn't been successful yet. Work continues on the basis of student projects. |
Start Year | 2014 |
Description | Nuclear Lamina |
Organisation | Pierre and Marie Curie University - Paris 6 |
Country | France |
Sector | Academic/University |
PI Contribution | Popdc null mutants |
Collaborator Contribution | Expertise in nuclear envelop related laminopathies. Null and knockin LMNA mutations to study genetic interaction |
Impact | not yet Grant application has been submitted |
Start Year | 2015 |
Description | Popdc and adenylate cyclase |
Organisation | University of Texas |
Department | Health Science Center at Houston |
Country | United States |
Sector | Academic/University |
PI Contribution | Popdc constructs, Tissue from knockout animals |
Collaborator Contribution | expertise in adenylate cyclases provides data for a jont publication |
Impact | not yet |
Start Year | 2016 |
Description | Popdc3 and Muscle Disease |
Organisation | Newcastle University |
Department | Institute of Genetic Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise in Popdc proteins |
Collaborator Contribution | Identification of patients with muscle disease |
Impact | not yet |
Start Year | 2016 |
Description | Popdc3 and Muscle Disease |
Organisation | University of Copenhagen |
Department | Section of Social Medicine |
Country | Denmark |
Sector | Academic/University |
PI Contribution | Expertise in Popdc proteins |
Collaborator Contribution | Identification of patients with muscle disease |
Impact | not yet |
Start Year | 2016 |
Description | The role Popdc proteins in the intracardiac nervous system |
Organisation | Dalhousie University |
Department | Department of Physiology and Biophysics |
Country | Canada |
Sector | Academic/University |
PI Contribution | The collaboration with the Dalhousie University lead to a discovery of a role of the Popdc proteins in the intracardiac nervous system (ICNS). This has not been previously seen and is a novel finding made by our collaborators in Canada. We provide our partners with the animal model (.i.e. zebrafish strain carrying a popdc1 S201F knockin mutation and the popdc1 null mutant line. We are currently investigating whether Popdc1 is expressed in ICNS neurons and whether the degeneration observed is caused by a primary defect in the ICNS. |
Collaborator Contribution | They made the discovery of the ICNS defect. A total of five applications to several funding organisations in Canada and by myself to the BHF is based on this exciting finding to further analyse the underlying mechanisms and the relevance for phenotype development. |
Impact | No publication as of now. |
Start Year | 2017 |
Description | Zebrafish cardiovascular physiology |
Organisation | Dalhousie University |
Department | Department of Physiology and Biophysics |
Country | Canada |
Sector | Academic/University |
PI Contribution | Providing zebrafish models of human heart and muscle disease. |
Collaborator Contribution | measurement of cardiac function Measuring by optical mapping conduction velocity intracardiac nervous system |
Impact | Schindler RF, Scotton C, Zhang J, Passarelli C, Ortiz-Bonnin B, Simrick S, Schwerte T, Poon KL, Fang M, Rinné S, Froese A, Nikolaev VO, Grunert C, Müller T, Tasca G, Sarathchandra P, Drago F, Dallapiccola B, Rapezzi C, Arbustini E, Di Raimo FR, Neri M, Selvatici R, Gualandi F, Fattori F, Pietrangelo A, Li W, Jiang H, Xu X, Bertini E, Decher N, Wang J, Brand T, Ferlini A (2016 ). POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. J Clin Invest.126:239-53. |
Start Year | 2015 |
Description | Zebrafish cardiovascular physiology |
Organisation | University of Innsbruck |
Country | Austria |
Sector | Academic/University |
PI Contribution | Providing zebrafish models of human heart and muscle disease. |
Collaborator Contribution | measurement of cardiac function Measuring by optical mapping conduction velocity intracardiac nervous system |
Impact | Schindler RF, Scotton C, Zhang J, Passarelli C, Ortiz-Bonnin B, Simrick S, Schwerte T, Poon KL, Fang M, Rinné S, Froese A, Nikolaev VO, Grunert C, Müller T, Tasca G, Sarathchandra P, Drago F, Dallapiccola B, Rapezzi C, Arbustini E, Di Raimo FR, Neri M, Selvatici R, Gualandi F, Fattori F, Pietrangelo A, Li W, Jiang H, Xu X, Bertini E, Decher N, Wang J, Brand T, Ferlini A (2016 ). POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. J Clin Invest.126:239-53. |
Start Year | 2015 |
Description | cAMP |
Organisation | University of Glasgow |
Department | Institute of Cardiovascular and Medical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise , animal models, identification of cAMP binding by Popdc proteins. Cell assays to test function. Antibodies. |
Collaborator Contribution | Pepetide scans to screen for protein domains involved in protein-protein interaction. |
Impact | not yet any outcomes. Collaboration has just started |
Start Year | 2016 |
Description | cAMP Nanodomains |
Organisation | University of Oxford |
Department | Department of Physiology, Anatomy and Genetics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | KI mouse models carrying mutations discovered in patients with cardiac arrhythmia and muscular dystrophy. |
Collaborator Contribution | Provides cAMP sensors (CUTie) to study specific cAMP nanodomains in myocytes of the KI mice to get an idea of the underlying mechanisms causing aberrant cardiac pacemaking and conduction in the mutants. |
Impact | nothing yet to report |
Start Year | 2018 |
Description | cAMP affinity of Popdc proteins |
Organisation | University of Kassel |
Department | Department of Biochemistry |
Country | Germany |
Sector | Academic/University |
PI Contribution | Expression constructs for Popdc proteins |
Collaborator Contribution | Expertise in protein expression and precise measurement of ligand affinity |
Impact | not yet |
Start Year | 2016 |
Description | crystallization |
Organisation | BioLog |
Country | Germany |
Sector | Private |
PI Contribution | We have introduced the Popdc protein to this community and designed the project. |
Collaborator Contribution | Kings college will generate NMR and protein crystallography data. The OPPF facility will generate the optimal construct for protein crystallization. A search for ligands that specifically bind to cAMP will be done with our partner at Imperial college. The search will be aided by more than 300 ligand derivatives synthesised by BioLog. |
Impact | Structural Biology Medicinal Chemistry Protein Biochemistry |
Start Year | 2013 |
Description | crystallization |
Organisation | Imperial College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have introduced the Popdc protein to this community and designed the project. |
Collaborator Contribution | Kings college will generate NMR and protein crystallography data. The OPPF facility will generate the optimal construct for protein crystallization. A search for ligands that specifically bind to cAMP will be done with our partner at Imperial college. The search will be aided by more than 300 ligand derivatives synthesised by BioLog. |
Impact | Structural Biology Medicinal Chemistry Protein Biochemistry |
Start Year | 2013 |
Description | crystallization |
Organisation | King's College London |
Department | Cardiovascular Division |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have introduced the Popdc protein to this community and designed the project. |
Collaborator Contribution | Kings college will generate NMR and protein crystallography data. The OPPF facility will generate the optimal construct for protein crystallization. A search for ligands that specifically bind to cAMP will be done with our partner at Imperial college. The search will be aided by more than 300 ligand derivatives synthesised by BioLog. |
Impact | Structural Biology Medicinal Chemistry Protein Biochemistry |
Start Year | 2013 |
Description | crystallization |
Organisation | King's College London |
Department | Randall Division of Cell & Molecular Biophysics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have introduced the Popdc protein to this community and designed the project. |
Collaborator Contribution | Kings college will generate NMR and protein crystallography data. The OPPF facility will generate the optimal construct for protein crystallization. A search for ligands that specifically bind to cAMP will be done with our partner at Imperial college. The search will be aided by more than 300 ligand derivatives synthesised by BioLog. |
Impact | Structural Biology Medicinal Chemistry Protein Biochemistry |
Start Year | 2013 |
Description | crystallization |
Organisation | Research Complex at Harwell |
Department | Oxford Protein Production Facility-UK (OPPF-UK) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We have introduced the Popdc protein to this community and designed the project. |
Collaborator Contribution | Kings college will generate NMR and protein crystallography data. The OPPF facility will generate the optimal construct for protein crystallization. A search for ligands that specifically bind to cAMP will be done with our partner at Imperial college. The search will be aided by more than 300 ligand derivatives synthesised by BioLog. |
Impact | Structural Biology Medicinal Chemistry Protein Biochemistry |
Start Year | 2013 |
Description | ion channel |
Organisation | Philipp University of Marburg |
Department | Institute of Physiology |
Country | Germany |
Sector | Academic/University |
PI Contribution | Collaboration on the identity of ion channels and pumps that interact with Popdc proteins. Collaboration has lead to one publication in the past. Further publications are in the pipeline or are currently in planning. |
Collaborator Contribution | Injection of mRNA into Xenopus oocytes and measurement of current by patch clamp analysis. |
Impact | Schindler RF, Scotton C, Zhang J, Passarelli C, Ortiz-Bonnin B, Simrick S, Schwerte T, Poon KL, Fang M, Rinné S, Froese A, Nikolaev VO, Grunert C, Müller T, Tasca G, Sarathchandra P, Drago F, Dallapiccola B, Rapezzi C, Arbustini E, Di Raimo FR, Neri M, Selvatici R, Gualandi F, Fattori F, Pietrangelo A, Li W, Jiang H, Xu X, Bertini E, Decher N, Wang J, Brand T, Ferlini A (2016 ). POPDC1(S201F) causes muscular dystrophy and arrhythmia by affecting protein trafficking. J Clin Invest.126:239-53. |
Start Year | 2011 |
Description | neuromuscular junction |
Organisation | Newcastle University |
Department | Institute of Genetic Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise into Popeye domain containing protein biology. Mouse and zebrafish knockouts |
Collaborator Contribution | Expertise in Neuromuscular junction related diseases, in particular Congenital Myasthenia Syndrome |
Impact | A grant application has been submitted. Genetics Medicine Neurology Biochemistry |
Start Year | 2015 |
Description | protein interaction |
Organisation | Max Planck Society |
Department | Max Planck Institute for Heart and Lung Research |
Country | Germany |
Sector | Academic/University |
PI Contribution | We generated protein extracts of heart and skeletal muscle of Popdc1 and Popdc2 mutant mice. |
Collaborator Contribution | Search for protein interaction partners of Popdc proteins. A number of novel protein interaction partners were identified through this collaboration. |
Impact | A manuscript describing the interaction with Ankyrin and the sodium channel Nav1.5 is currently in preparation. |
Start Year | 2011 |
Description | sinus bradycardia |
Organisation | University of Manchester |
Department | Institute of Cardiovascular Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Breeding of Popdc null mutants and pathophysiological characterisation |
Collaborator Contribution | Sinus node preparations physiology and pharmacology to identify the underlying causes for the pacemaker dysfunction in Popdc animals. |
Impact | Poster at the European Society of Cardiology Meeting 2013 in Amsterdam |
Start Year | 2012 |
Description | BBC Film 2012 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | A film was produced which is now internationally distributed http://www.bbc.co.uk/programmes/b01kpvj1 http://vimeo.com/45783883 |
Year(s) Of Engagement Activity | 2012 |
URL | http://www.offthefence.com/detail/of-hearts-and-minds/1256350/ |
Description | Imperial Festival |
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 | My group participated in a stand on the Imperial Festival which was designed by the BHF. It was a Ring Toss game, which formed the basis for some talk about our work on the Popeye genes. It was also shown at some other Science Festivals in Cheltenham and Norwich and some of my students also went there as well to man the stand. |
Year(s) Of Engagement Activity | 2019 |
Description | Native Scientist |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 2 english biology classes who also have had German as their language visited the Goethe institute in London. Four scientists including myself gave a brief presentation (i.e.10 min.) of their research for small groups in a speed dating format. I have talked about the impact of adrenergic stimulation on heart performance and the role of the Popeye domain containing genes in this process. The pupils were asked to do some physical activity (knee bends) and recorded before and after their heart rate. Using PPT presentation we subsequently discussed the biochemical processes involved. |
Year(s) Of Engagement Activity | 2017 |
URL | https://nhliblog.wordpress.com/2017/06/16/how-does-the-heart-to-adapt-to-stress-prof-brand-explained... |
Description | School Visit (German School in Richmond) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | Approx. 20 pupils have attended each year my lecture. In each year, one of the pupils joined my lab for a brief laboratory apprenticeship. They went on to study Medicine. The other one plans to go into Biology. |
Year(s) Of Engagement Activity | 2012,2013 |