The Integrated Stress Response and Oligodendrocyte Survival After Spinal Cord Injury

Grants and Contracts Details

Description

Previous work identified the temporal aspects of elongation initiation factor 2á (eIF2á) phosphorylation as the therapeutic target to reduce endoplasmic reticulum stress response (ERSR)-induced oligodendrocyte (OL) death and enhance functional recovery after contusive thoracic SCI. If eIF2á is not phosphorylated for long enough or for too long, apoptotic OL cell death results and locomotor performance does not recover. In the current proposal, we propose: Aim 1. Examine upstream regulators of eIF2á for their ability to block ERSR/ISR-induced OPC/OL death. The integrated stress response (ISR) is a cytoprotective mechanism that maintains proteostasis (cellular homeostasis). Four kinases (Perk, Pkr, Gcn2, Hri), activated by different stressors, phosphorylate eIF2á, which inhibits global translation and enhances ERSR gene expression. We will use a combination of previously optimized gain and loss of function in vitro OPC/OL and in vivo SCI assays that utilize pharmacological inhibitors as well as Hri-/-, Pkr-/-, and Gcn2-/-mice. Aim 2. Examine the role of the downstream ISR effector Atf4 in SCI. Atf4 is the major contributor to ISR/ERSR toxicity and our preliminary data document activation of Atf4 after SCI or in ER-stressed OPCs. These studies will determine whether Atf4 is a mediator of OL death, white matter damage, and functional decline in a contusive SCI model. Aim 2A will use WT and Atf4-/- mice. Aim 2B will determine whether Atf4 inhibition by adaptaquin (a hypoxia-inducible factor prolyl hydroxylase domain enzyme – HIF-PHD) reduces ERSR-mediated OL/OPC cell death and improves SCI outcome.
StatusActive
Effective start/end date6/15/183/31/23

Funding

  • University of Louisville: $90,820.00

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