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 p38alpha isoform in microglia proinflammatory cytokine production, and found that suppression of p38alpha 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 p38alpha 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 p38alpha 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 p38alpha 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 p38alpha to improve outcomes following a TBI. To this end we need to answer: 1) When can p38alpha be targeted; i.e., what is the optimal therapeutic window after TBI? 2) Where and how can p38alpha be targeted; i.e., does p38alpha 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, p38alpha-dependent inflammatory responses in multiple cell types synergize and cross-talk to drive neurologic impairments. We will test the hypothesis that suppression of p38alpha 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 p38a inhibitor.
Aim 2. Define the contribution of p38a in resident microglia versus infiltrating macrophages to TBI-induced impairments.
Aim 3. Determine how p38alpha in other CNS inflammatory cell types (astrocytes and endothelial cells) contributes to injury-induced responses.
Traumatic brain injury represents a major unmet medical need for which there is no effective therapy to improve outcome and prevent the cognitive impairment, long-term neurologic morbidity, or increased risk of dementia and other medically intractable complications. Successful completion of these studies will define when, where and how the important inflammatory kinase p38alpha can be targeted for beneficial outcomes. Our results will provide a foundation for the future clinical development of p38alpha inhibitors for head injury.
|Späni, Claudia B; Braun, David J; Van Eldik, Linda J (2018) Sex-related responses after traumatic brain injury: Considerations for preclinical modeling. Front Neuroendocrinol 50:52-66|
|Zhou, Zhengqiu; Bachstetter, Adam D; Späni, Claudia B et al. (2017) Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes. J Neuroinflammation 14:75|
|Maphis, Nicole; Jiang, Shanya; Xu, Guixiang et al. (2016) Selective suppression of the ? isoform of p38 MAPK rescues late-stage tau pathology. Alzheimers Res Ther 8:54|
|Van Eldik, Linda J; Carrillo, Maria C; Cole, Patricia E et al. (2016) The roles of inflammation and immune mechanisms in Alzheimer's disease. Alzheimers Dement (N Y) 2:99-109|
|Andreasson, Katrin I; Bachstetter, Adam D; Colonna, Marco et al. (2016) Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem 138:653-93|