The current drugs used in treating MS decrease the likelihood of myelin damage by modulating the immune system, but do not actually promote the repair of myelin. Therefore, if the myelin has already been damaged or lost, the current set of drugs cannot restore myelin, which is needed to restore the function of the associated nerve. To design drugs that can overcome this challenge, more knowledge about the inner workings of myelin-forming cells is needed. Our goal is, therefore, to understand the inner workings of the myelin-forming cells, the so-called "cellular signals" that control myelin repair, in order to design and produce successful myelin repair therapies. Myelin repair therapies have the potential to impact both relapsing-remitting MS and progressive MS as in both conditions there is myelin loss that negatively impacts brain function.

We have recently discovered that when myelin-forming cells lack a protein called Csk myelination is enhanced. This enhancement of myelin occurs both during normal brain development and during myelin repair in a mouse model for MS in which myelin damage was induced. Our proposal seeks to further investigate the effect of Csk loss, in order to learn what cellular signals are altered in Csk-deficient cells, and then to hone in specifically on the cellular signals that enable those cells to become significantly better at myelin repair. We plan to take two approaches. In the first approach, we will follow up on our "lead candidate," a protein complex called AMPK, which we have already discovered to be higher than normal in the Csk-deficient cells. AMPK is a crucial cellular signal that has previously been shown to act as a cellular energy sensor, for instance, responding to changing energy levels to influence cell metabolism. In the current study we propose to test whether AMPK loss or AMPK stimulation has the ability to alter myelin repair. Excitingly, we will be using an already FDA-approved drug, metformin, which potentiates AMPK activity and has been used safely for many years for the treatment of diabetes, to learn if this drug promotes myelin repair. Also, as we have now identified the cellular energy sensor AMPK as a potential signal in the control of myelination, this opens up a new avenue for myelin repair drug discovery. Little is currently known regarding how energy metabolism in myelin-forming cells impacts their ability to undergo myelin repair, and this study may therefore lead to future studies in which we can screen other existing drugs that are known to influence cellular energy states for potential effects on myelin repair. In our second approach, we will use molecular analysis tools to screen for all possible changes in genes or proteins that may be altered in the Csk-deficient myelin-forming cells. This more comprehensive approach is designed to uncover previously unknown pathways or cellular signals that regulate myelin repair and could therefore open up new avenues for therapy development.

By learning more about cellular signals that can enhance myelin repair, our next goal will be to translate these findings into drug discovery in which we investigate ways to harness these signals to help repair myelin, first in animal models, then in MS patients. Because one of the compounds we are testing in this study is already FDA-approved for the treatment of diabetes, if we see a beneficial effect on myelin repair in mouse models we will be able to more quickly move to clinical trials for MS patients. The second approach is more exploratory but will greatly improve our currently limited understanding of how effectively brain cells can make myelin and, down the road, should improve the pipeline of novel drug targets for preclinical testing for the treatment of MS.