[R01] Endothelin signaling in neural stem cell homeostasis and remyelination
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2030-07-31
Importo max: 424.106 EUR
Paese: US
Descrizione
PROJECT ABSTRACT
Endogenous neural stem cells play a crucial role in neurogenesis and gliogenesis in the adult healthy brain and
following injury or disease. In response to demyelination, or the loss of myelin sheaths surrounding axons,
endogenous neural stem cells contribute to repair by upregulating gliogenesis and differentiating into myelinating
oligodendrocytes. However, there is a gap in our current understanding of the mechanisms regulating adult
neural stem cell-mediated remyelination. In particular, it remains unclear how neurovascular interactions within
the stem cell niche respond to demyelination, and how this shapes neural stem cell behavior. We previously
identified Endothelin-1 as a novel regulator of neural stem cells during development. In the adult brain, we find
that endothelial cell-derived Endothelin-1 signals to neural stem cells as part of the neurovascular unit. Loss of
this signaling pathway promotes gliogenesis from quiescent neural stem cells. Therefore, we hypothesize that
Endothelin-1 signaling maintains adult neural stem cell quiescence, preventing differentiation in both the healthy
and demyelinated brain. We will test this hypothesis through the following specific aims: In aim 1, we will use
conditional knockout mice and primary cell culture to determine if Endothelin-1 signaling regulates neural stem
cell quiescence in the healthy adult mouse brain. In aim 2, we will use knockout mice and the cuprizone toxicity
demyelination mouse model to determine the role of Endothelin-1 signaling in neural stem cell-derived
remyelination. Overall, these results will provide critical insight into the mechanism of Endothelin-1 signaling in
adult neural stem cells and the feasibility of targeting this pathway to enhance remyelination.
Istituzione: UNIVERSITY OF NOTRE DAME
PI: Katrina L Adams
Progetto: 5R01NS140152-02
Settori: National Institute of Neurological Disorders and Stroke
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