TRC 4 Grants
Congratulations to the four winners in the Department of Anesthesiology, Critical Care and Pain Medicine who successfully secured TRC 4 grants! The PIs are Drs. Yafen Liang, Cynthia Ju, Yang Yang, and Yankai Wen. The funding ranges from $100-500k for 16 months. More information can be found on each below.
Yafen’s TRC4
Title: Prevention of Hemorrhagic Shock-induced Acute Kidney Injury by Targeting Hypoxia-sensitive ATP4A with Pantoprazole: A Prospective Randomized Controlled Trial
Hemorrhage is the leading cause of death in civilian and military trauma worldwide. Organ failure including acute kidney injury (AKI), as a consequence of hemorrhage, is the third leading cause of death for trauma patients after hemorrhage and traumatic brain injury. AKI occurs in up to 50% of trauma patients presenting with hemorrhagic shock. AKI is associated with increased short and long-term mortality, progression to chronic kidney disease, prolonged hospitalization, and increased healthcare costs. Preventive and therapeutic options are extremely limited. One of the main causes of post-hemorrhagic shock AKI involves renal hypoperfusion/ischemia and reperfusion injury. In Dr. Eltzschig’s (study co-PI) lab, they identified a novel endogenous kidney protection pathway during acute hypoxia/ischemia involving proton pump inhibitors. We propose a single-center, randomized, pragmatic trial to determine whether intravenous administration of proton pump inhibitor will reduce acute kidney injury in trauma patients presenting with hemorrhagic shock. If the current proposal is successfully completed, PPIs such as pantoprazole could be given very early after injury or potentially even prophylactically to prevent AKI in hemorrhagic shock trauma patients. This would represent the first clinical approach to reduce AKI to improve trauma patient outcomes. This study is in collaboration with the trauma team (Dr. Lillian Kao) and the emergency department (Dr. Bobrow), at Memorial Hermann TMC.
Cynthia’s TRC4
Title: Investigation of the therapeutic potential of eosinophils to attenuate trauma and combat casualty-related liver injury
Trauma-related liver injuries pose significant challenges in both civilian and battlefield settings. Our published have studies demonstrated that eosinophils infiltrate the liver after acute injury and play a profound protective function. With the TRC4 funding, we plan to develop a protocol of propagating human eosinophils from cord blood progenitors and evaluate the efficacy of human eosinophils in attenuating traumatic liver injury and promoting tissue repair using mouse models of liver injury caused by ischemia/reperfusion injury and hemorrhagic shock.
Yang’s TRC4
Title: A Novel Role of Eosinophil-Specific Cyclooxygenase-2 in Trauma-Related Liver Injury
We have previously shown that an alarmin, IL-33, is released during liver ischemia/reperfusion (IR) injury and that it activates eosinophils to attenuate tissue damage. Our screening of downstream target revealed cyclooxygenase (COX)-2 upregulation in eosinophils in response to IL-33 stimulation. We generated eosinophil-specific Cox2 knockout mice and found them to be more susceptible to liver IR injury, which occurs during trauma-related liver injury. In the proposed studies we will investigate the hypothesis that eosinophils, through COX2-mediated suppression of neutrophil extracellular traps formation, protect against traumatic liver injury.
Yankai’s TRC4
Title: Role of Neutrophil-derived Hypoxia-Inducible Factor 1 Alpha in Liver Injury
In the context of liver trauma, liver ischemia/reperfusion (I/R) injury emerges as a critical concern, particularly in the postoperative management of severe cases. Our initial forays, employing single-cell RNA sequencing, have unveiled a pronounced enrichment of hypoxia pathway genes in a distinct cluster of liver neutrophils present during I/R injury. Leveraging a genetically engineered mouse model deficient in neutrophil-specific hypoxia-inducible factor (Hif)1α, we observed a marked resistance to I/R injury, suggesting a pivotal role for neutrophil-derived Hif1α in injury exacerbation. Our forthcoming research endeavors will rigorously investigate the role of neutrophil-specific Hif1α in promoting neutrophil extracellular traps through an F3-mediated pathway, eventually contributing to the aggravation of liver injury.