DOI
https://doi.org/10.25772/45RA-JQ45
Author ORCID Identifier
0000-0001-5048-1736
Defense Date
2020
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Neuroscience
First Advisor
Babette Fuss
Second Advisor
Pamela Knapp
Third Advisor
James Lister
Fourth Advisor
Gregory Walsh
Fifth Advisor
Yan Zhang
Abstract
LPA, produced by the lysoPLD activity of ATX, binds its cognate receptors and regulates the development of multiple brain cells, including oligodendrocytes (OLGs). OLGs progress through a lineage from precursor (OPC) to early OLG to immature OLG, until finally the cells mature and enwrap axons to enable saltatory conduction and provide trophic support. The studies in this dissertation characterized the receptors LPA4 and LPA6 as inhibitors of OPC differentiation. Western blot analysis of MS patient lesion tissue found a negative correlation between ATX levels and levels of LPA4 and LPA6. A previously created homology model for LPA4 was used to design and prepare compounds to target LPA6. The PRESTO-TANGO GPCR assay system determined two of these compounds to be partial agonists for the non-Edg LPA receptors. Using a developing zebrafish in vivo model as well as in vitro studies in rat primary OLGs, one of these compounds, GL-8-28, inhibited OLG differentiation gene expression. In further studies, siRNA mediated-knockdowns for Lpar6 in the rat primary OLGs were insufficient to disrupt OLG differentiation gene expression. However, triple knockdown of Lpar1, Lpar4 and Lpar6 significantly increased OLG differentiation gene expression. Because knockdowns of Lpar6 failed to reduce transcription of the target gene below 50 percent, we analyzed Lpar6 null mouse brains, and found a modest increase in myelin proteins. Taken together, these studies provide evidence for a novel inhibitory role of these receptors in OLG development, and potentially novel therapeutic targets in the treatment of multiple sclerosis.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
10-12-2020