Targeting activin receptors as a novel approach to promote myelin repair in the central nervous system

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Oligodendrocytes are cells in the central nervous system that make myelin, an insulating layer around nerves that allows their normal functioning. Damage to myelin occurs in multiple sclerosis, contributing to lifelong problems with movement and sensation. Myelin repair can occur following this damage, and involves stem cells in the brain that multiply, survive and become new oligodendrocytes. However, as multiple sclerosis progresses, repair is less efficient and nerves don't function properly. Understanding what makes the stem cells multiply, survive, and become new oligodendrocytes is important in discovering new therapies that encourage myelin repair in MS. My studies show that a factor called activin-A is present in the brain during myelin repair, the stem cells in the injured brain have the receptors to respond to activin-A, and activation of these receptors can make these stem cells multiply, survive and become new oligodendrocytes in a dish. I predict that activin receptor activation in stem cells in the central nervous system drive myelin production and repair, and that activin receptors represent promising potential targets for a regenerative therapy for multiple sclerosis. The overall aim of my proposal is to understand how activin receptors control stem cell behaviour during myelin production and repair. The first objective is to identify when activin receptors could be activated on stem cells when myelin is being made or repaired, by looking at expression of activin receptors in the central nervous system of animal models.As there are multiple forms of activin receptors, the second aim is to determine which one of these can stimulate stem cells, by seeing if stem cells can still respond to activin-A when specific forms of activin receptors are no longer expressed. Loss of expression of specific activin receptors will be done using cutting edge modification of the stem cell DNA. These stem cells will then be analysed for ability to multiply, survive and become new oligodendrocytes, and signal activation patterns inside the cell.The third aim is to find out if other molecules that are known to activate activin receptors other than activin-A can also make stem cells multiply, survive, become oligodendrocytes and make myelin. Their expression in animal models when myelin is being made or repaired will be tested, and their effects on stem cell multiplication, survival and ability to become oligodendrocytes will be investigated.The fourth aim is to find out whether activin receptor activation on stem cells is needed for myelin to be made or repaired, using an animal model where the receptors aren't present on the stem cells and seeing whether myelin is still made or repaired. We will also test whether stimulating activin receptors, using activin-A or the other molecules identified above, is able to drive myelin repair in an animal model where it normally doesn't happen, to model the failed myelin repair in multiple sclerosis.The funding from this award would allow me to expand my research group, set up my independence and ask these important questions, which I believe could lead to the discovery of new strategies to encourage repair in multiple sclerosis. I believe that this research will show us the importance of activin receptors for stem cells in driving myelin repair, so that we can build on these findings to develop therapies for multiple sclerosis that stimulate these receptors.