Utilizing CNS tissue derived extracellular vesicles to identify biomarkers of remyelination and demyelination

Project Summary Multiple sclerosis (MS) is the most common neurodegenerative disease in young adults. Despite the identification of several molecules that could potentially promote remyelination, the lack of biomarkers of this process is a major roadblock in the translation of these findings to the clinic. Extracellular vesicles (EVs) are a promising platform for biomarker identification and newer methods enable their isolation and characterization from tissues of interest. Our long-term goals are to identify novel biomarkers of demyelination and remyelination to promote identification of novel therapeutic strategies for repair and remyelination in MS. The objectives of this R21 application are to identify biomarkers of demyelination and remyelination by studying altered proteins and lipids in tissue-derived and plasma-derived EVs in a mouse model of demyelination. The rationale for this project, supported by preliminary data, is that tissue derived EVs can be isolated and characterized from mouse or human tissue and profiled using proteomics analyses to identify meaningful biomarkers of the underlying disease process. The proposed research study will pursue two specific aims: 1) to identify proteins in tissue- and plasma- derived EVs specific for demyelination and remyelination in a mouse model of MS and 2) to identify lipids in tissue- and plasma-derived EVs specific for demyelination and remyelination in a mouse model of MS. For both aims we will utilize the cuprizone induced toxic demyelination model and obtain corpus callosum tissue and blood from mice at various time-points in the demyelination and remyelination phases, followed by isolation of EVs. In aim 1 the EVs will undergo proteomics analyses while in aim 2 the EVs will undergo lipidomics analyses. Statistical analyses will then help identify proteins and lipids in EVs that are specific to demyelination and remyelination stages and could serve as potential biomarkers for these processes. This project is innovative in that it proposes to test a novel hypothesis that tissue-derived and plasma-derived EV proteomics could be used to identify novel markers or demyelination and remyelination and also utilizes cutting-edge tools to accomplish the proposed aims. The proposed research is significant because it could identify novel biomarkers for use in trials of therapeutic agents that could promote myelin repair in this chronic disabling neurological disorder.