Functional Link Between Innate Immunity, Oligodendrocyte Development, and Myelina

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Health Relatedness: Over 400,000 Americans are afflicted with multiple sclerosis (MS), with severe disability ultimately affecting ~ 85% of the total MS population. Disability in MS is primarily due to demyelination and axonal injury. Axonal injury itself is tied to demyelination as significant axonal transection occurs in acute demyelinatng lesions, and gradual axonal loss is linked to chronic demyelination. Preventing demyelination and enhancing remyelination are essential to preserving CNS integrity and promoting recovery in MS. We propose that the TLR2-MyD88 pathway is central to both the process of demyelination and failure of remyelination in MS. Our hypothesis is that activation of the TLR2-MyD88 pathway in innate immune cells leads to inflammatory destruction of oligodendrocytes, myelin, and axons, whereas, activation of this same pathway in oligodendrocytes blocks their normal maturation thus preventing remyelination. Long-term goals: Our long-term goals are to define molecular pathways in MS, that play essential roles in the injury and repair process, for use as therapeutic targets. In this proposal our goal is to determine the importance of the TLR2-MyD88 pathway in causing demyelination and axonal injury, and in inhibiting remyelination, through in vivo and in vitro modeling. Research Approach: In each aim, the common goal is to determine the function of the TLR2-MyD88 pathway in MS model systems using demyelination, oligodendrocyte death, axonal injury, neuronal death, oligodendrocyte maturation and remyelination as end points. In aim 1 cuprizone mediated demyelination is used to study the impact of the TLR2-MyDBB pathway on the process of demyelination and the contribution in innate immunity to this process. Relevant knock-out mice are used to establish functional significance of TLR2 and MyD88. Quantitative assessments of demyelination, oligodendrocyte death, axonal injury, neuronal death, and inflammation will be made. In aim 2 we will study the impact of the TLR2-MyD88 pathway on remyelination using the cuprizone and lysolecithin models. Quantitative assessments of remyelination, oligodendrocyte maturation, oligodendrocyte survival, neuronal survival, and axonal integrity will be made.