Targeted cell-specific deletion of Kir4.1 channels to determine their functions in oligodendrocytes

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.

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.

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.