Investigation of the Protein kinase C alpha signaling in the development of sepsis-associated liver failure.

• Applicant: Professor Dr. Adrian Press
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 542813223

Sepsis is a life-threatening organ dysfunction caused by the dysregulated host response to infection, highly associated with prolonged ICU and hospital stays and higher mortality. Hepatocytes in the liver control significant aspects of the host response, including inflammation, e.g., through synthesizing acute phase proteins or removing alarmins, energy metabolism, and blood pressure. However, the liver's elimination capacity drops in sepsis, resulting in cholestasis. Treatment directed to restore liver function is not yet available, and impaired excretory liver failure function ultimately results in dysbiosis and significantly contributes to the dysregulated host response highly associated with mortality. Therefore, preventing organ failure or supporting organ regeneration in the critically ill is a fundamental goal in current sepsis research. Understanding the pathomechanism of sepsis-associated liver failure in hepatocytes stimulates tissue-directed therapies that could support liver function. Protein kinase C (PKC) signaling is a crucial protein that controls the trafficking of canalicular transporter in hepatocytes. Those canalicular transporters are lost in sepsis-associated liver failure, causing the accumulation of toxic metabolites that favor the dysregulation of the infection host response. Since the efficient restoration of liver function in sepsis can potentially increase survival significantly, mechanistic research of sepsis-associated excretory liver failure is crucial to advance understanding of the complex pathophysiology. This work investigates the roles of PKCalpha in hepatocytes in sepsis to determine how the enzyme's change in activity contributes to liver failure in sepsis.

• DFG Programme: Research Grants