Myeloid cell ferroptosis in hemorrhagic stroke

Hemorrhagic stroke (HS) is a devasting acute injury with less than a 50% 1-year survival rate. Clinically, HS presents a complex problem, and most medical intervention is focused on maintenance of blood pressure, coagulation intracranial pressure, edema, inflammation, and oxidative stress. Following acute injury, immune cell infiltration can promote clearance of the hematoma; however, in many cases can contribute to inflammatory tone and drive neurodegeneration resulting secondary injury. The immune response in HS is not well understood, and currently, the literature remains divided the beneficial role of immune cell recruitment in HS. This fellowship proposes to investigate how myeloid ferroptosis, an oxidative form of cell death contributes to secondary injury after HS. The central hypothesis of this fellowship is that myeloid cell ferroptosis drives neurodegeneration during secondary injury after HS. To test this hypothesis, we propose two aims: 1) Drive myeloid ferroptosis by knockout of glutathione peroxidase 4 (GPX4), the key regulator of ferroptosis, and 2) Prevent myeloid ferroptosis by knockout of acyl-CoA synthetase long-chain family member 4 (ACSL4). Using a combination of genetic and pharmacological approaches we will investigate pathological mouse behavior after HS, immune cell response and polarization to hematoma, and therapeutic intervention after HS. The long-term goal of this proposal is to identify a subset of responsive myeloid cells that are susceptible to ferroptosis and drive secondary injury after HS that can be modulated pharmacological to improve HS outcome. We suspect that this paradigm will transcend HS pathology and may be generalized to other pathologies of oxidative stress providing a novel therapeutic approach to improve clinical outcomes. Project Number: 1F32HL182385-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Clint Upchurch | Institution: UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE, VA | Award Amount: $78,040 | Activity Code: F32 | Study Section: Special Emphasis Panel[ZRG1 F03C-A (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F32HL18238501