Sigma-1 Receptor Agonists as a Novel Therapeutic for Circadian Rhythm Disruption-Induced Fatigue
Abstract
Circadian rhythm disruption (CRD) is the “greatest contributor” to fatigue in cockpits inthe United States Air Force (USAF). Prolonged CRD in uncontrolled combat operations causessevere fatigue symptoms, including cognitive impairments such as increased reaction time anddegraded awareness of new situations. While various interventions have been employed totemporarily alleviate fatigue symptoms, there is a need for directly restoring cognitiveabilities of aircrew members. This PI proposes a novel countermeasure for CRD induced fatigue—using sigma-1 receptor (S1R) agonists to restore mitochondrial function in neurons and thuscognitive abilities.The research goal of this project is to investigate the therapeutic efficacy of selected S1Ragonists in relieving CRD-induced cognitive degradation in our rodent model. We hypothesizethat S1R agonism restores neuron energy metabolism and neuroplasticity, and thus alleviatesfatigue and improves cognitive abilities. Four objectives underlie the research goal: 1) to evaluatethe efficacy of two S1R agonists in improving mice’s responses to learning, memory, and motorcoordination; 2) to characterize the changes in energy metabolism after administering S1R agonistsin three cognitive-related brain regions of CRD mice; 3) to assess the effect of S1R agonists onmitochondrial function that impacts metabolic homeostasis and neuroplasticity; and 4) toinvestigate the molecular mechanism of the interaction between S1R and its agonists. The noveltyof the proposed project lies in three aspects: 1) using sigma-1 agonists as a novel fatigueintervention paradigm; 2) employing polyacrylamide gel matrices comparable to the brain’srigidity to study mitochondrial functions of neurons; and 3) utilizing nanotechnology to investigateinteractions between S1R and its selected agonists.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 09, 2018
- Source ID
- FA95501710423
Entities
People
- Kai Shen
Organizations
- Air Force Office of Scientific Research
- Savannah State University
- United States Air Force