Metabolic adaptations to sepsis

Sepsis, characterized by life-threatening organ dysfunction due to a dysregulated host response to infection, remains a critical global health challenge. While conventional research has focused primarily on the inflammatory cascade, accumulating evidence highlights a critical, early metabolic dysregulation during sepsis. Understanding these metabolic disturbances is vital to developing strategies to preserve or reverse organ function. My previous work demonstrated that septic mice rapidly enter a hypometabolic state resembling torpor, and identified the Integrated Stress Response (ISR) as a central activated pathway. Mechanistically, the ISR preserves cellular homeostasis by prioritizing the translation of cytoprotective mRNAs (e.g., molecular chaperones) while halting general protein synthesis—a highly energy-demanding process. However, while initially adaptive, chronic ISR activation triggers cell death. The precise role of the ISR in driving metabolic collapse during sepsis remains unresolved. In this project, I hypothesize that persistent activation of the ISR shifts the host from an adaptive hypometabolic state into a maladaptive metabolic failure, ultimately causing organ dysfunction. To test this, I will deploy complementary genetic and pharmacological tools to inhibit the key ISR effector ATF4 in a murine cecal ligation and puncture (CLP) model. I will track systemic metabolic alterations using invasive and non-invasive phenotyping, and delineate the downstream molecular networks via Western blotting, qRT-PCR, proteomics, and metabolomics. Finally, I will mechanically manipulate target metabolic pathways to define the causal links between ISR activity, metabolic arrest, and organ failure. These outcomes will provide fundamental insights into the molecular regulation of metabolism during severe infection and uncover novel therapeutic targets to reverse sepsis-induced organ dysfunction.

Publications