Role of Nrf2 in oligodendrocyte development and ischemic response ? Project Summary White matter injury is a crucial component of ischemic stroke pathophysiology. In addition to local neuronal death, ischemia damages oligodendrocytes, the myelin-producing cells of the central nervous system. This causes secondary damage to myelinated axons connecting brain regions, effectively increasing the scope of neuronal injury. Stroke susceptibility varies with age, and the juvenile period is characterized by greater stroke recovery than at other ages. Previous work from our lab has shown that in the juvenile brain, oligodendrocytes and myelinated axons are resistant to ischemic injury. Interestingly, the juvenile period is the peak of central nervous system myelination, which imposes heavy metabolic demands on oligodendrocytes. One possible mechanism of juvenile oligodendrocyte ischemic resistance is that active myelination requires increased antioxidant capacity that confers protection from ischemic injury. However, the mechanisms by which oligodendrocytes cope with the unique metabolic demands of myelination remain unknown. Analysis of acutely isolated juvenile and adult oligodendrocytes uncovered differential transcriptional regulation of Nrf2, a transcription factor best known for driving glutathione synthesis and metabolism in response to oxidative stress. Nrf2 plays a role in ischemic responses in several cell types in the central nervous system, and it can protect oligodendrocytes from reactive oxygen species. Moreover, global Nrf2 knockouts develop vacuolar myelin degeneration as they age. However, the role of Nrf2 in mediating oligodendrocyte development and response to ischemia remains unknown. The current proposal investigates oligodendrocyte reactive oxygen species management in developmental and pathological contexts. We will utilize transgenic Cre/lox mouse technology and in vitro systems to manipulate Nrf2 specifically in the oligodendrocyte lineage and determine its role during myelination. The Cre/lox system will also be utilized in conjunction with the Herson laboratory juvenile stroke model to investigate the role of oligodendroglial Nrf2 in juvenile ischemic resistance. Understanding the mechanisms by which the juvenile brain copes with ischemic injury can inform treatment options for patients of different ages and provide insight into central nervous system development.
Stroke severity and symptoms can vary widely with age. Juvenile oligodendrocytes are resistant to stroke despite comparable neuronal vulnerability. However, there are no current strategies for treating stroke victims of different ages. This project seeks to understand the underlying mechanisms of protection relative to age- dependent stroke pathology, which is a crucial step for tailoring post-stroke treatment to the specific needs of patients.
