Grants and Contracts Details
Description
A key mechanism that drives pathophysiology progression in many CNS disorders is dysregulated
neuroinflammatory responses, especially inflammatory cytokine overproduction, from abnormally
activated glia. Although most neuroinflammation research has focused on microglia as the primary
immune cell of the brain, activated astrocytes also play important roles. The molecular mechanisms
underlying astrocyte activation responses and the consequences for disease progression are complex and
understudied.
Our research is focused on a key cell signaling protein that contributes to neuroinflammatory responses in
Alzheimer’s disease (AD): the p38alpha MAP kinase (p38). Activation of p38 occurs early in AD and can
lead to chronic neuroinflammation that has neurodegenerative consequences, and small molecule p38
inhibitors are currently in AD clinical trials. Most research on p38 signaling has been done in microglia or
neurons. This project will use novel mouse models with genetic knockout (KO) specifically in astrocytes
and well-characterized human brain tissue to explore p38 signaling in astrocytes and clarify how this
pathway links neuroinflammatory changes and AD-relevant synaptic/neuronal dysfunction.
Our central hypothesis is that astrocyte p38 activation in response to inflammatory stress stimulates
production of the inflammatory cytokine IL-33, which then propagates proinflammatory responses and
leads to AD-relevant neuronal/synaptic damage.
Status | Active |
---|---|
Effective start/end date | 7/1/24 → 6/30/27 |
Funding
- BrightFocus Foundation: $300,000.00
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