Microglia responses to CNS injury: Targeting p38 MAPK signaling

Grants and Contracts Details


Microglia are the resident tissue myeloid cell in the brain. Acute isolation and molecular profiling of adult microglia have clearly identified a microglia-specific gene expression profile not found in other macrophage populations, or other cells in the CNS. As a molecular and functionally unique population of cells, microglia exhibit a remarkable ability to survey the brain and rapidly undergo a spectrum of responses to insults or tissue damage. These coordinated responses normally result in protection against injury, but can be dysfunctional and exacerbate or even cause neurological disease. An added layer of complexity occurs when monocytes are recruited to the brain following disease or injury. As a functionally distinct population, newly recruited monocytes/macrophages make different contributions to disease progression compared to microglia. One of the top canonical pathways in microglia/macrophages is the p38 MAPK pathway, a well-established signaling pathway important in stress responses. In the last funding period, we documented the importance of the p38Ą isoform in microglia proinflammatory cytokine production, and found that suppression of p38Ą can prevent the inflammatory response that causes subsequent neuronal/synaptic damage. In two mouse models of diffuse traumatic brain injury (TBI), we found that deletion of p38Ą in myeloid cells was associated with decreased microglia activation, and a rescue of vestibulomotor deficits, cognitive impairments and synaptic protein loss. Our data demonstrating the importance of p38Ą in regulating key functions of macrophages/microglia that are altered by a brain injury provides a strong precedent for further mechanistic and translational studies. We have now developed an exceptionally specific small molecule p38Ą inhibitor (termed MW150), that is CNS-penetrant, has drug-like properties, and no adverse effects at very high doses. MW150 is a novel reagent with high translational relevance for future therapeutic development. As a foundation for future development, we now propose to address mechanistically how to target p38Ą to improve outcomes following a TBI. To this end we need to answer: 1) When can p38Ą be targeted; i.e., what is the optimal therapeutic window after TBI? 2) Where and how can p38Ą be targeted; i.e., does p38Ą in other inflammatory cell types besides microglia (infiltrating macrophages, astrocytes, endothelial cells) contribute to neuroinflammatory responses after TBI? Our studies will provide key mechanistic information about how injury-induced, p38Ą-dependent inflammatory responses in multiple cell types synergize and cross-talk to drive neurologic impairments. We will test the hypothesis that suppression of p38Ą signaling in appropriate therapeutic windows and appropriate cell types after CNS injury can lead to selective, beneficial outcomes. Our aims are: Aim 1. Establish the post-injury therapeutic window for efficacy of our small molecule p38Ą inhibitor. Aim 2. Define the contribution of p38Ą in resident microglia versus infiltrating macrophages to TBI-induced impairments. Aim 3. Determine how p38Ą in other CNS inflammatory cell types (astrocytes and endothelial cells) contributes to injury-induced responses.
Effective start/end date5/1/154/30/20


  • National Institute of Neurological Disorders & Stroke: $1,645,912.00


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