All of the current therapies available for treating multiple sclerosis are anti-infllammatory agents that target the immune system, and there are no approved drugs that promote repair of demyelinated lesions, which is the underlying cause of neurological disability. Our long-term goal is to define how CNS lipids are regulated by changes in brain hormones and how this affects neurological disease. The overall objective in this application, which is the first step toward achieving our long-term goal, is to identify lipid-related genes that are important during remyelination and define how the lipidome changes during demyelination and remyelination. Our central hypothesis is that hormones promote myelination through transcriptional regulation of genes involved in lipid metabolism, and that regulation of lipids is critical for successful remyelination. Our hypotheses have been formulated based on studies showing that thyroid hormone regulates lipid-related genes in the brain and during oligodendrocyte progenitor cell (OPC) differentiation, which is an important step in myelination. In addition, several lipid classes including sterols and lysophosphatidic acids have been implicated in remyelination. The rationale that supports the proposed research is that it will identify lipid pathways for the development of new therapies for promoting myelin repair. The central hypothesis will be evaluated with the two following specific aims: (1) Identify lipid-related genes regulated by nuclear receptors and required for OPC differentiation; and (2) Map myelin lipid changes during remyelination. In the first aim, an OPC differentiation assay will be used to evaluate a panel of nuclear receptor ligands that have been implicated in myelination. RNA-sequencing will then be performed to identify lipid-related genes involved in OPC differentiation and membrane process extension. For the second aim, brain lipids will be isolated from an inducible conditional knockout mouse model of demyelination based on the Plp-CreERT;Myrffl/fl strain. Mass spectrometry analysis will be performed to profile the brain lipidomic changes in demyelinating and remyelinating phases of the disease course. The proposed research is innovative, in the applicant?s opinion, because two orthogonal approaches are being used to synergistically identify new lipid pathways of importance in remyelination. Upon completion of this proposed research, it is expected that one or more lipid pathways involved in CNS remyelination will be identified. This contribution is expected to be significant, because it will increase knowledge about how lipids are regulated during remyelination and may reveal a novel target for therapeutic intervention in diseases affected by demyelination. These studies will also provide necessary preliminary data for a competitive R01 grant application in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103638-09
Application #
10242613
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Davani, Behrous
Project Start
2012-07-15
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
9
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Type
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Zhu, Qingfu; Heon, Mikala; Zhao, Zheng et al. (2018) Microfluidic engineering of exosomes: editing cellular messages for precision therapeutics. Lab Chip 18:1690-1703
Pacelli, Settimio; Basu, Sayantani; Berkland, Cory et al. (2018) Design of a cytocompatible hydrogel coating to modulate properties of ceramic-based scaffolds for bone repair. Cell Mol Bioeng 11:211-217
Wessinger, Carolyn A; Kelly, John K; Jiang, Peng et al. (2018) SNP-skimming: A fast approach to map loci generating quantitative variation in natural populations. Mol Ecol Resour 18:1402-1414
Zhang, Peng; Crow, Jennifer; Lella, Divya et al. (2018) Ultrasensitive quantification of tumor mRNAs in extracellular vesicles with an integrated microfluidic digital analysis chip. Lab Chip 18:3790-3801
Klaus, Jennifer R; Deay, Jacqueline; Neuenswander, Benjamin et al. (2018) Malleilactone Is a Burkholderia pseudomallei Virulence Factor Regulated by Antibiotics and Quorum Sensing. J Bacteriol 200:
Abisado, Rhea G; Benomar, Saida; Klaus, Jennifer R et al. (2018) Bacterial Quorum Sensing and Microbial Community Interactions. MBio 9:
Hill, Tom; Unckless, Robert L (2018) The dynamic evolution of Drosophila innubila Nudivirus. Infect Genet Evol 57:151-157
Bandyopadhyay, Arnab; Wang, Huijing; Ray, J Christian J (2018) Lineage space and the propensity of bacterial cells to undergo growth transitions. PLoS Comput Biol 14:e1006380
Kaplan, Sam V; Limbocker, Ryan A; Levant, Beth et al. (2018) Regional differences in dopamine release in the R6/2 mouse caudate putamen. Electroanalysis 30:1066-1072
Reiner, David J; Lundquist, Erik A (2018) Small GTPases. WormBook 2018:1-65

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