The role of gasdermin E-mediated necrosis in atherosclerosis. 01/11/2023 - 31/10/2025


Cell death is a prominent feature of advanced plaques with a major impact on atherogenesis and plaque destabilization. According to morphological studies, the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrotic cell death. Gasdermins have recently been identified as essential effector molecules in different types of programmed necrosis by forming pores in the plasma membrane. Besides the canonical caspase-1/inflammasome pathway that activates gasdermin D, gasdermin E was recently identified as an alternative key executioner of programmed necrosis after cleavage by caspase-3. Although numerous studies underscored the importance of caspase-3-mediated cell death in atherosclerosis, the role and impact of gasdermin E-mediated necrotic cell death is currently unknown. Nonetheless, necrosis has become an important and attractive research target to stabilize rupture-prone plaques. Therefore, this research proposal defines the following objectives: (1) extensive analysis of gasdermin E-mediated necrosis in both human and mouse plaques, (2) identification of the molecular mechanisms of gasdermin E-mediated necrosis in atherosclerosis, (3) inhibition of plaque necrosis using gasdermin E knockout mice, and (4) characterization of autophagy as a natural defense mechanism against gasdermin E-mediated necrosis. In general, this project will allow a significant advance in the fundamental understanding of regulated necrosis in atherosclerosis.


Research team(s)

Project type(s)

  • Research Project