Monday, May 5, 2025
5/5/2025
Suspect Treat Organ failure Prevent Sepsis Mortality (STOP Sepsis Mortality) - Project Summary/Abstract Despite enormous investments in research over the last 30 years, pediatric sepsis remains a leading cause of in-hospital death, particularly in underserved and minoritized populations. Sepsis is defined as rapidly progressive, life-threatening organ dysfunction (OD) due to an immune dysregulation as a response to infection. In the U.S. over 75,000 children are admitted for sepsis annually with an associated mortality rate of 5 to 20%. Effective timely sepsis management (early/accurate diagnosis and appropriate treatment) is exacerbated by varying sepsis phenotypes resulting in high heterogeneity in sepsis presentations and responses. Sepsis phenotypes can result in significant variability in the immune response by disrupting metabolism and adenosine triphosphate (ATP) levels, affecting critical cellular functions including those needed to fight infections. The pathophysiology of sepsis is linked to an energetic crisis combined with immune-mediated inflammation. Specifically, cells shift their energy generation from aerobic oxidative phosphorylation (OXPHOS) to less-efficient glycolysis. Cellular energetic deficiency leads to excess accumulation of reactive oxygen species (ROS) and subsequently to oxidative stress, inflammation, and cell death. Studies have highlighted a mesenchymal stem cell (MSC)-related improvement in energetics that is partially achieved by the transfer of bioactive molecules such as miRNAs and proteins carried by secreted extracellular vesicles (MSC-EVs). Neonates and young children are particularly vulnerable to energy deficits during sepsis due to their limited energy reserves, higher metabolic rates, and immature organ systems. Early sepsis recognition and timely treatment with appropriate antibiotics, IV fluids and/or vasopressors can reduce mortality. Additionally, there is no therapy that directly targets the pathophysiologic changes of sepsis such as the concurrent disrupted energy-generating metabolic processes and immune dysregulation, especially in organs most affected by sepsis such as the brain and the lungs. To develop new therapeutic protocols for sepsis, our team has been investigating the use of MSC-EVs in alleviating sepsis-induced immune and metabolic dysfunction with encouraging results. In summary, I have established a program that aims to decrease sepsis mortality in the pediatric population by 1) using an AI-guided early identification tool, 2) performing sepsis phenotyping and a digital twin patient model to predict personalized treatment response and 3) developing a cutting-edge extracellular vesicle-based therapeutic protocol. I have made significant contributions to the scientific community by providing mentorship to students from diverse backgrounds and service to professional societies, peer review panels and journal editorial boards. I’m committed to creating a diverse team and an inclusive environment with the goal of decreasing sepsis mortality and potential long-term effects and improving the lives of many vulnerable children and especially those from marginalized populations.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).