Investigating the Role of Proton-Sensing G Protein Coupled Receptors in Trauma and Hemorrhagic Shock

Major traumatic injury, particularly when accompanied by hemorrhagic shock (HS), results in disruption of endothelial barrier integrity, leading to vascular leakage and tissue edema. Patients with traumatic brain injury (TBI) are especially vulnerable to HS, as a two-fold increase in mortality is observed when TBI is accompanied by HS. The proton sensing G protein-coupled receptors (PsGPCRs), GPR4 and GPR68, are expressed on cerebral endothelial cells and are regulated by extracellular pH. These receptors play a critical role in maintaining endothelial barrier function and may be pathologically activated in the acidotic state generated during HS. We have recently established a murine model of combined TBI and HS that closely recapitulates human injury. Preliminary data from this model demonstrates increased endothelial permeability when HS is introduced. Additionally, we have observed upregulation of cerebral endothelial PsGPCR expression following murine TBI, suggesting a potential role for these receptors in mediating endothelial activation and dysfunction in response to injury. Central Hypothesis: PsGPCRs mediate endothelial activation and increased cerebral permeability following TBI, and their activation is exacerbated by the systemic acidosis resulting from HS, leading to worsened cerebral edema and neurobehavioral outcomes. To test this hypothesis, we propose three specific aims: 1. Investigate how trauma and hemorrhagic shock influence the expression of cerebral endothelial PsGPCRs. 2. Identify how PsGPCR activation, induced by trauma and hemorrhagic shock, affects cerebral endothelial cell permeability and signaling. 3. Assess the impact of PsGPCR inhibition on neurobehavioral deficits following HS+TBI This work will fill a critical gap in our understanding of the molecular mechanisms underlying endothelial barrier dysfunction after traumatic injury and hemorrhagic shock. The results of this study may identify PsGPCRs as novel therapeutic targets for limiting cerebral edema and improving neurobehavioral outcomes for those suffering with TBI. Project Number: 1K08GM164635-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Grace Niziolek | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $200,613 | Activity Code: K08 | Study Section: Special Emphasis Panel[ZRG1 ISB-G (85)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11350253