Obstructive sleep apnea is associated with neural injury, including motoneuronal dysfunction. The overall goal of the proposed studies is to advance mechanisms by which intermittent hypoxia (IH) injures motoneurons in an effort to unveil novel directions for development of therapies for sleep apnea. Focusing on cellular mechanisms of IH injury, we have found that IH results in a marked unfolded protein response and apoptosis in hypoglossal and facial motoneurons, while motor trigeminal and occulomotor neurons confer resistance. We have identified several important differences in the IH response between susceptible and resistant motoneurons. In this proposal, we seek to test each difference as a potential avenue for treating motoneuronal injury. First, susceptible motoneurons show activation of an endoplasmic reticulum (ER) sensor, PERK, in response to IH. PERK is activated when BiP, the master regulator chaperone of the ER, is released from PERK to chaperone unfolded proteins. In Aim 1, we will test the role BiP plays in protecting motoneurons from IH injury. IH susceptible motoneurons accumulate a pro-apoptotic protein CHOP. Thus we suspect impaired degradation of CHOP in susceptible motoneurons contributes to their demise (Aim 2). IH cause significant injury to other organelles and cellular processes. Which of these are secondary to ER injury or which are primary will be explored. SIRT1 may play a more global role in responding to the metabolic challenges of IH (Aim 3). Here again, crosstalk between BiP, CHOP and SIRT1 pathways will be determined. Having identified in mice a differential IH susceptibility across upper airway motoneurons and having identified key mediators in the ER and oxidative stress injury pathways, we will next examine these mechanisms in post-mortem human upper airway motoneurons. This work is designed to advance novel therapeutics for nerve injury in obstructive sleep apnea. PUBLIC HEALTH RELEVANCE: Obstructive sleep apnea is a common disorder in children as well as in adults, and in adults, sleep apnea is associated with peripheral nerve and brain injury. Using a mouse model of the sleep apnea oxygenation patterns we have identified a significant injury to the neurons that innervate the upper airway. The proposed studies are designed to identify novel pathways for therapies to prevent and/or reverse the injuries.