Current Research

After contusive spinal cord injury (SCI), primary loss of neural tissue is followed by secondary damage that exacerbates functional deficits and can be targeted for neuroprotection. Components of the secondary injury include death of neurons and oligodendrocytes, destruction of axons, and demyelination. The resulting damage is further amplified by neurotoxic inflammation that is mediated by microglia and monocyte-derived macrophages. After SCI, persistent inflammation may spread to non-injured portions of the central nervous system limiting functional recovery and facilitating secondary complications such as chronic pain and/or depression. Our current research projects focus on mechanisms underlying SCI-associated oligodendrocyte loss, demyelination, and, deleterious neuroinflammation.

Cell type-specific effects of the integrated stress response pathway after traumatic spinal cord injury (supported by the NINDS award 1R01NS138333, collaboration with Dr. Sujata Saraswat-Ohri)

Various forms of cell damage/dysfunction activate the integrated stress response (ISR) kinases (PERK, HRI, GCN2, PKR) to phosphorylate the translation factor eIF2α (peIF2α). Inhibition of general protein synthesis and upregulation of the transcription factors ATF4 and CHOP follows. Initially, ISR activation attempts to restore cellular homeostasis. If that fails, prolonged ISR follows and cell death may occur. In addition, HRI-mediated ISR may facilitate inflammation. This project tests the novel hypothesis that after contusive SCI, distinct ISR kinases activate unique cell-specific effector mechanisms with diverse consequences on recovery. Specifically, in oligodendrocytes, a moderate/transient increase of peIF2α downstream of PERK may restore homeostasis. Conversely, in inflammatory cells, the HRI-peIF2α-ATF4/CHOP pathway enhances cytotoxic neuroinflammation. In addition, HRI may drive excessive ISR activation killing oligodendrocytes. To test this hypothesis we use cell type specific deletions of Hri or Perk genes in mice. Such a genetic approach is complemented with pharmacological inhibitors. Importantly, ISR modulation may become a new therapeutic target for small molecule drugs to promote neuroprotection and/or reduce cytotoxic neuroinflammation following traumatic CNS injury.

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