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Project

Regulated necrosis as a pharmacological target in atherosclerosis.

Morphological studies indicate that the vast majority of dying cells in advanced human atherosclerotic plaques undergo necrosis. Although the role of necrosis in atherosclerosis remains ill-defined, a growing body of evidence suggests that necrotic death stimulates atherogenesis and plaque instability through induction of inflammation and enlargement of a central necrotic core. For a long time, necrosis in advanced plaques has been considered as a merely accidental and uncontrolled form of cell death, but recent data indicate that it can also occur in a regulated fashion through induction of necroptosis. However, it should be noted that other examples of regulated necrosis such as ferroptosis are emerging. Moreover, gasdermins have recently been identified as essential effector molecules in different types of programmed necrosis by forming pores in the plasma membrane. Because regulated necrosis is considered an important pharmacological target to stabilize plaques, the following objectives are defined: (1) identification of ferroptosis and gasdermin E-mediated necrosis in both human and mouse plaques, (2) inhibition of both processes via genetic or pharmacological approaches, and (3) characterization of autophagy as a natural defense mechanism against necrosis in atherosclerosis. This project may lead to the discovery of novel anti-atherosclerosis therapies, and will allow a significant advance in the fundamental understanding of regulated necrosis in atherosclerosis.
Date:1 Jan 2023 →  Today
Keywords:ATHEROSCLEROSIS, NECROSIS
Disciplines:Cell death, Vascular diseases, Pharmacology not elsewhere classified