Role of membrane damaging effector proteins in innate immune cell-mediated tissue injury

Lytic forms of programmed cell death, pyroptosis and necroptosis, play an integral role in driving innate inflammatory responses and tissue damage in a range of inflammatory diseases (reviewed in Lawlor KE Immunity 2024 57:429). However, the specific role of the membrane-damaging pyroptotic Gasdermin (GSDMD & GSDME) and necroptotic Mixed lineage kinase domain-like (MLKL) effector proteins are ill-defined. Moreover, there is very little known about the role of the downstream plasma membrane rupture molecule Ninjurin-1 (NINJ1) in models of inflammatory disease. This project will use mice deficient in these key effector proteins, and inhibitory drugs, to explore their role in renal and cardiac tissue damage. This project will offer the opportunity to be trained in a range of techniques, including preclinical human/mouse models of disease, primary cell culture, western blotting, specialised cell death assays, immunofluorescence, qPCR, ELISA, tissue analysis, histopathology, flow cytometry and CRISPR/Cas9 gene editing.