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Tyro3 in myelination and remyelination

In multiple sclerosis (MS) the protective sheath around nerves, known as myelin, is damaged and lost. This loss disrupts electrical impulses and exposes nerves to immune attack, leading to their death. Current MS therapies suppress the immune response but do not promote repair or prevent disease progression. We have shown that a protein known as Tyro3 improves myelin production and repair. The goal of this study is to establish how Tyro3 works, and the comparative benefit it is likely to provide.

Aims

This project aims to define the importance of Tyro3 to myelin repair and assess what functional benefits Tyro3-mediated repair might provide

The loss of myelin ensheathing axons, a process known as demyelination, impairs nerve function and exposes axons to further inflammatory attack. Following a demyelinating event, some spontaneous remyelination occurs but it is often incomplete, and ultimately fails. We have previously identified that Gas6, a ligand for the TAM (Tyro3, Axl and Mertk) family of tyrosine kinase receptors, directly increases myelination in vitro, and that loss of Gas6 leads to increased disease severity and to delayed recovery in an animal model of CNS demyelination. The provision of exogenous Gas6 promotes repair in two separate animal models of MS, suggesting that enhancement of repair via TAM activation is a practical therapeutic goal.

We have now established that the pro-myelinating effect of Gas6 is transduced through the Tyro3 receptor on oligodendrocytes, and that the loss of Tyro3 has consequences for the myelination of nerves in the CNS. This project will further explore the role of Tyro3 during developmental myelination, using a mouse strain in which the Tyro3 gene has been deleted. In particular, we will assess the structure of the Nodes of Ranvier, the gaps in the myelin sheath which are essential to signal conduction in the nerve, as well as the development of the myelin-producing oligodendrocytes. We will also examine the contribution of Tyro3 to myelin repair following demyelination.

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