Monday, May 12, 2025
5/12/2025
THE ROLE OF PTEN IN MICROGLIAL PATHOBIOLOGY AFTER EXPOSURE TO REPETITIVE MILD TBI - Repetitive mild traumatic brain injury (r-mTBI) is one of the strongest risk factors for developing neurodegenerative diseases. To date, no disease modifying therapies have been developed to prevent the long- term consequences of TBI. There is a need to advance our current understanding of the cellular mechanisms driving the long-term neurological deficits after TBI, as this could lead to the identification of novel therapeutic targets. Neuroinflammation mediated by resident microglia is a common feature of human and animal models of TBI. Factors governing the propagation and persistence of disease associated microglial responses in the chronic sequelae of TBI remain elusive. We have established a mouse model of r-mTBI that recapitulates many features of human TBI and thus represents a translationally relevant preclinical platform. From this model we have generated a molecular library of microglia gene profiles, at a range of timepoints post-injury that provides a unique and detailed time-course of the microglial neuroinflammatory response to r-mTBI. Particularly, we reveal deficits in energy bioenergetics, cytokine signaling, lipid metabolism, and a pro-inflammatory signature of microglia at chronic timepoints, which appear to be driven by the activation of Phosphatase and Tensin Homolog (PTEN) signaling. PTEN is a lipid phosphatase that antagonizes phosphatidylinositol 3-Kinase signaling, a critical node vital for regulating cell survival, energy bioenergetics, autophagy and inflammation. PTEN is highly expressed in myeloid cells, and its dysregulation can trigger the activation of inflammatory responses. Multiple cell types express PTEN, thus PTEN inhibitors lack the specificity needed to target PTEN signaling in microglia. In a pilot study, we have shown that PTEN deletion in myeloid cells after 1 mo dampens disease associated microglial responses and proinflammatory signature in our model. In this new application, we plan to extend these studies to further clarify the role of PTEN in regulating microglia responses in the context of TBI and demonstrate whether microglia specific PTEN deletion can mitigate TBI mediated neuroinflammation/neurodegeneration and chronic functional outcomes. We will compare TBI- dependent responses in the presence or absence of PTEN deletion to reveal microglial specific targets that correlate with favorable outcomes after r-mTBI and represent novel therapeutic targets. We will achieve this by utilizing a tamoxifen inducible mouse model that will specifically target PTEN deletion in microglia and not other myeloid cells (Hexbcre+/PTENfl/fl). We will induce PTEN deletion using three therapeutic time-windows (i.e., pre-injury, early and delayed), and examine functional and pathobiological outcomes, scRNAseq profiles and functional activities of microglia at 6 mo post-injury. Our goal is to clarify the role of PTEN as a negative regulator of microglial pathobiology in the chronic sequelae of r-mTBI, and to identify unique gene signatures and reparative mechanisms in microglia induced by PTEN deletion that can be explored as novel microglial specific targets in TBI and other neurodegenerative diseases where neuroinflammation is a critical contributor.
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