Roles of CHPG in Human-Induced Pluripotent Stem Cell-Derived Oligodendrocytes

Project Details

Description

This is an Exploration - Hypothesis Development Award application that is designed to test the hypothesis that a small molecule able to cross the blood-brain barrier called 2-chloro-5-hydroxyphenylglycine or CHPG will enhance differentiation of human induced pluripotent stem cell-derived oligodendrocyte lineage cells. We propose that use of this drug will ultimately lead to a rescue of myelin loss such as occurs in Multiple Sclerosis. The application addresses the Research Focus Central Nervous Regenerative Potential in Demyelination and is directed to identify factors that promote remyelination in human cells. For the last 30 years my laboratory has focused on studies aiming to reverse demyelination in mouse models of Multiple Sclerosis. Our results have resulted in the identification of a drug with potential therapeutic relevance as we find that injection of CHPG into the abdomen results in the reversal of losses in myelin and behavioral deficits seen in a demyelinating mouse model. The CHPG effects are localized to the brain as they are prevented by both injection of a CHPG blocking agent in the brain lesion site, and by the loss of the CHPG receptors in brain glial cells called astrocytes. The current study pursues the therapeutic utility of the mouse studies to now explore CHPG effects on human cells. In preliminary work we find that CHPG enhances differentiation of fetal human oligodendrocytes in culture, raising the exciting possibility that manipulation of oligodendrocytes, cells that make myelin, by CHPG may be clinically important. To more thoroughly examine this, we will now extend work to accessible human induced pluripotent stem cells that have been pushed to mature into brain cells, including oligodendrocytes. We examine CHPG effects on these human myelin producing cells. Studies will explore effects on proliferation, death, and differentiation, as well as examine cellular mechanisms that underlie CHPG actions. Upon completion of this study, we will establish whether a small molecule, able to cross the blood-brain barrier and remyelinate demyelinating lesions, is effective on human cells found in a demyelinating lesion site. The long-term objective is to determine whether manipulation of the cell by CHPG will be effective in reversing demyelination, such as occurs in the devastating Multiple Sclerosis.

StatusActive
Effective start/end date9/1/22 → …

Funding

  • U.S. Army: $235,500.00

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