Targeted cell-specific deletion of Kir4.1 channels to determine their functions in oligodendrocytes
Lead Research Organisation:
University of Portsmouth
Department Name: Sch of Pharmacy & Biomedical Sciences
Abstract
Oligodendrocytes are specialised cells of the brain and spinal cord that form myelin. Myelin is the insulating layer around nerve axons and is essential for rapid conduction of information. As such, the normal functioning of oligodendrocytes is essential for Lifelong Health and Wellbeing. Most oligodendrocytes in the brain are generated around birth and during the first years of development. However, oligodendrocytes continue to be generated in the adult brain and this is important for replacing cells that are lost during normal ageing. Notably, generation of oligodendrocytes in the ageing brain can be inadequate for reparative processes, and this is important in age-related loss of white matter integrity and cognitive function. The mechanisms underlying white matter defects in the ageing brain are unresolved. Now, we have identified a specific cell membrane ion channel called Kir4.1 that is crucial for oligodendrocyte function. We propose to determine the mechanisms by which Kir4.1 regulates the generation of oligodendrocytes in the developing and ageing brain. This work meets the BBSRC Research Priority of Ageing Research (Lifelong Health and Wellbeing), and will make a significant contribution to addressing BBSRC core bioscience and thematic strategic priorities.
Technical Summary
The project is basic research to examine the fundamental importance of the Kir4.1 potassium channel subtype in oligodendrocytes. We have demonstrated that oligodendrocytes strongly express Kir4.1 and that there is severe oligodendrocyte dysfunction following global ablation of Kir4.1 in conventional knock out (KO) mice. However, the precise function of Kir4.1 channels in oligodendrocytes are unknown and it is not clear why they are so critically important for myelin-formation. Our studies highlight the crucial importance of Kir4.1 in oligodendrocytes, but in the global Kir4.1 KO mouse the effects on oligoderocytes represent developmental defects, and it is not possible to distinguish between direct and indirect effects. Determination of the precise functions of Kir4.1 in oligodendrocytes requires targeted disruption of these channels. We will use tamoxifen-inducible CreERT2/loxP gene targeting to create the first inducible KO mice in which the Kir4.1 gene is specifically disrupted in oligodendrocytes and their progenitors. Generation of these mouse strains will enable us to control the temporal and cell-specific expression of Kir4.1, with which we will be able to make major advances in our understanding of the functions of oligodendrocyte Kir4.1 in the developing and ageing brain.
Planned Impact
The main beneficiaries of our research are other scientists, and dissemination of research findings will be through the normal routes of publications, reviews and presentations at meetings. In the longer term, our research is also likely to be of interest to clinicians, patient groups, and the wider public. I will make every effort with the UoP to publicise support we receive from all sources, and to explain our research objectives and potential of the results we gain. When possible, I will make myself available to speak to local and national media on the importance of how grant support drives our much needed fundamental research into glial cells, and how this is relevant to the general public.
It is not anticipated that any directly patentable data will be obtained from this project, but I will continue to work closely with RK&T in the UoP to identify the wider impact and commercialization potential of our research.
It is unlikely that this research will lead to new drug design in the immediate future, but it will hopefully help identify potential targets that will lead to the future development of novel therapies aimed at promoting glial cell function in their critical support of neurons. This would have considerable wider impact. Through the IBBS and Brains Trust, I will use several routes to communicate our findings to the potential user groups and general public. I will present live demonstrations to local schools, and write articles for specialised magazines for patients to whom my research will ultimately be directy relevant.
It is not anticipated that any directly patentable data will be obtained from this project, but I will continue to work closely with RK&T in the UoP to identify the wider impact and commercialization potential of our research.
It is unlikely that this research will lead to new drug design in the immediate future, but it will hopefully help identify potential targets that will lead to the future development of novel therapies aimed at promoting glial cell function in their critical support of neurons. This would have considerable wider impact. Through the IBBS and Brains Trust, I will use several routes to communicate our findings to the potential user groups and general public. I will present live demonstrations to local schools, and write articles for specialised magazines for patients to whom my research will ultimately be directy relevant.
People |
ORCID iD |
Arthur Butt (Principal Investigator) |
Publications
Rivera A
(2016)
A Central Role for ATP Signalling in Glial Interactions in the CNS.
in Current drug targets
Papanikolaou M
(2020)
A critical role for the inward rectifying potassium channel Kir7.1 in oligodendrocytes of the mouse optic nerve.
in Brain structure & function
De Amorim VCM
(2020)
Agathisflavone modulates astrocytic responses and increases the population of neurons in an in vitro model of traumatic brain injury.
in Naunyn-Schmiedeberg's archives of pharmacology
Rivera A
(2016)
Decreased Regenerative Capacity of Oligodendrocyte Progenitor Cells (NG2-Glia) in the Ageing Brain: A Vicious Cycle of Synaptic Dysfunction, Myelin Loss and Neuronal Disruption?
in Current Alzheimer research
Rivera AD
(2022)
Epidermal Growth Factor Pathway in the Age-Related Decline of Oligodendrocyte Regeneration.
in Frontiers in cellular neuroscience
Brasko C
(2017)
Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS.
in Brain structure & function
Leoni G
(2014)
Immunoablation of cells expressing the NG2 chondroitin sulphate proteoglycan.
in Journal of anatomy
Rivera AD
(2021)
Keeping the ageing brain wired: a role for purine signalling in regulating cellular metabolism in oligodendrocyte progenitors.
in Pflugers Archiv : European journal of physiology
Description | We have: (1) developed a new transgenic mouse strain; (2) discovered novel functions for a number of ion channels and neurotransmitter receptors in promoting neural cell integrity and myelination; and (3) identified key changes in ion channels and neurotransmitters in ageing white matter. These data have been presented at a number of conferences, and to the public in lectures and lab visits. A number of full papers have been published. |
Exploitation Route | The new functional roles for cellular targets discovered in this project could be taken forward by other academics and the pharmaceutical industry. We have provided evidence that specific ion channels in glia are essential for brain function and integrity. |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
URL | http://www.port.ac.uk/institute-of-biomedical-and-biomolecular-science/cell-biology-and-pharmacology/arthur-butt/ |
Description | The findings to date have been used to inform other scientists, members of the public, and strengthen links with industry. |
First Year Of Impact | 2014 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Societal |
Description | ARUK Pilot Grant - co-PI with Southampton University |
Amount | £35,000 (GBP) |
Funding ID | ARUK-PPG2014B-2 |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 12/2014 |
End | 11/2015 |
Title | Aging mouse oligodendrocyte progenitor cells |
Description | Microarray dataset |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | The data was published in a paper |
Description | 2013 Southampton University Neuroinflammation group |
Organisation | University of Southampton |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are examining human ageing tissue provided by the collaboration |
Collaborator Contribution | Provision of human tissue and knowledge of human neuropathology |
Impact | New directions on the changes in glia in the ageing brain resulting in a pilot grant from the ARUK |
Start Year | 2014 |
Description | 2014 Prof Christian Giaume, Paris |
Organisation | College of France |
Country | France |
Sector | Academic/University |
PI Contribution | We have brought the expertise in oligodendrocyte biology |
Collaborator Contribution | Prof Christian Giaume has brought the expertise in gap junctions and CNS metabolism. He will also provide the facilities for the planned experiments. |
Impact | We have been successful in obtaining an Entente Cordiale Fellowship for the PDRA to be seconded to Prof Christian Giaume's lab in Paris to perform a series of key experiments that are not possible in the host institute. |
Start Year | 2014 |
Description | Olivier Raineteau, INSERM, Lyons |
Organisation | École normale supérieure de Lyon (ENS Lyon) |
Department | INSERM U846 (Stem-cell and Brain Research Institute) |
Country | France |
Sector | Public |
PI Contribution | Experimental design, hosting researchers, writing and publishing papers |
Collaborator Contribution | Experimental design, hosting researchers, writing and publishing papers |
Impact | Publications |
Start Year | 2017 |
Description | Professor Silvia Lima Costa, Bahia University, Brazil |
Organisation | Federal University of Bahia |
Country | Brazil |
Sector | Academic/University |
PI Contribution | Experimental design, hosting researchers, writing and publishing papers, hosting and attending bilateral workshops |
Collaborator Contribution | Funding (Brazil), experimental design, hosting researchers, writing and publishing papers, hosting and attending bilateral workshops |
Impact | Bilateral meetings and publications. |
Start Year | 2017 |
Description | Southampton University |
Organisation | University of Southampton |
Department | Southampton Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Data production and analysis, experimental design, paper writing |
Collaborator Contribution | Provision of tissue, analysis, design, writing |
Impact | Two publications and presentations at meetings |
Start Year | 2017 |
Description | 2013 Conference (Birmingham, UK) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | IUPS July 21-26, Birmingham, UK. Expression and function of Kir7.1 in neurons and glia of the CNS.M Papanikolaou, J Hallett, A Lewis, A Butt Collaborations and increased job prospects for PhD student |
Year(s) Of Engagement Activity | 2013 |
Description | 2013 December Anatomical Society Meeting, Newcastle |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Discussions about the impact of our work and possible future collaborations with a group in Ireland Academics have visited my lab |
Year(s) Of Engagement Activity | 2013 |
Description | 2013 Laboratory Visit (My labs, Portsmouth) |
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 | 25 people toured my labs as part of 'Dementia week', which sparked questions on the value of fundamental research to the potential cure of neurological diseases Feedback indicated new appreciation for the research going on in our university and the value of funds received from research councils and charities |
Year(s) Of Engagement Activity | 2013 |
Description | 2013 Public Lecture (Portsmouth) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Public/other audiences |
Results and Impact | 100 members of the public attended a series of public lectures on 'Inside the World of the Brain', which sparked questions and discussion on the research we do, how it generates new knowledge, and ultimately lead to the development of potential therapies for neurological diseases. Very positive feedback from members of the public on the value of our fundamental research and monies provided by the research councils |
Year(s) Of Engagement Activity | 2013 |
Description | 2014 June Padue Seminar and visit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Undergraduate students |
Results and Impact | 100 undergraduate and postgraduate students attended the talk, together with academics from the University of Padua, which resulted in lively discussions, exchange of ideas, establishment of new collaborations, and discussion of future student exchanges and fellowships. We have had exchange students from University of Padua working in the PI's lab. |
Year(s) Of Engagement Activity | 2014 |
Description | 2014 March University of Paris |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | New collaboration was established Exchange of students from France to work in my lab |
Year(s) Of Engagement Activity | 2014 |
Description | 2014 October Dublin Seminar |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | 15 students attended my workshop, which sparked discussions about the significance of glial cells in neuropathology Students have reported increased interest in glial cells in neuropathology |
Year(s) Of Engagement Activity | 2014 |
Description | 2014 September ISRT visit London |
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 | Policymakers/politicians |
Results and Impact | Meeting with funders of ISRT to promote understanding of spinal research and secure future funding. Lab visit |
Year(s) Of Engagement Activity | 2014 |
Description | 2014 September IoP Seminar |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | ~100 students attended my seminars, which sparked questions and discussions Students have requested further information on glial cell biology and their roles in pathology |
Year(s) Of Engagement Activity | 2014 |
Description | 2014 September SoNG meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | A great deal of interest in the posters presented by the PDRA and PhD students, resulting in job offers and collaborations New discussions with SAL Scientific, Southampton, to examine potential for grant to NC3Rs |
Year(s) Of Engagement Activity | 2014 |
Description | 2014 September Southampton Dementia conference |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Considerable interest inn the poster presentations of the PDRA and PhD students, resulting in offers of jobs for them, and potential collaborations New collaboration with Dr Roxanne Carare, Southampton, on changes in glial cells in human Alzheimer's disease and Bipolar Disorder brain tissue |
Year(s) Of Engagement Activity | 2014 |
Description | 2015 BBB Conference Southampton |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Interaction between basic scientists and clinicians - developed greater understanding of the clinical needs |
Year(s) Of Engagement Activity | 2015 |
Description | 2015 Euroglia Meeting Bilbao |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Presentation sparked a great deal of interest and ideas for future experiments and collaborations Discussions with other researchers led to considerable interest in utilising our spinal cord slice model |
Year(s) Of Engagement Activity | 2015 |
Description | 2015 FENS Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Presentation sparked many interesting discussions and ideas for future experiments Discussions with other researchers led to considerable interest in utilising our spinal cord slice model |
Year(s) Of Engagement Activity | 2015 |
Description | 2015 October UPAN Laboratory Tour |
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 | Talk sparked a great deal of interest and discussions The members of the public requested further information on our research |
Year(s) Of Engagement Activity | 2015 |
Description | 2015 September ISRT Network Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other academic audiences (collaborators, peers etc.) |
Results and Impact | Poster presentation sparked questions and discussions, leading to potential collaborations and directing future work. After the presentation, we have established further experiments to be performed. |
Year(s) Of Engagement Activity | 2015 |
Description | International Workshop, Brazil 2013 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Advanced School in Developmental Neurobiology, Rio de Janeiro, Brazil, Nov 25 2013. "Regulation of gliogenesis and neurogenesis in the adult brain", by Arthur M. Butt Established potential collaborations with the local postgraduate neuroscience programme and identified potential candidates for PhD in spinal research in the UK. |
Year(s) Of Engagement Activity | 2013 |
Description | Living with Dementia, Southampton UK Jan 2016 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | A mixed audience of PPI, academics, clinicians and funders, with the purpose of promoting understanding and bilateral communication. Considerable interest amongst PPI. |
Year(s) Of Engagement Activity | 2016 |