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.

Grant Number: 1R21NS140780-01A1
NIH Institute/Center: NIH
Principal Investigator: Pavan Bhargava