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Dr Murray Clarke

Dr Murray Clarke

Murray Clarke is accepting applications for PhD students.

Murray Clarke is available for consultancy.


Research Interests

We investigate how cell death affects the local tissue environment and in particular how necrosis drives sterile inflammation. We have a special interest in the pathogenesis of atherosclerotic plaques, which are characterized by chronic inflammation and an accumulation of apoptotic and necrotic cells. Much of our work focuses on the key inflammatory cytokine IL-1α, which acts as a powerful danger signal upon release from dead cells. However, our recent work has shown that an elaborate molecular system controls IL-1α in a conditional and cell type-dependent manner to prevent inappropriate activation. In addition, we also investigate the basic mechanisms that control IL-1α and IL-1β secretion and novel factors that control these pathways.

Specific areas of research:

  • Intracellular IL-1R2 controls IL-1α: IL-1R2 has a signal peptide that targets it for secretion. However, lots of IL-1R2 is cytosolic, where it inhibits IL-1α activity. We are investigating what cell-type specific mechanisms control this mislocalisation.
  • Role of IL-1α and IL-1R2 in atherosclerosis: IL-1 appears to play a key role in atherosclerosis. We are determining how IL-1R2 controls inflammation after necrotic death of cells within the plaque
  • Can IL-1R2 lessen graft rejection: Rejection of experimental vessel grafts is driven by damaged endothelial cell-derived IL-1α.
  • Failed phagocytosis in atherosclerosis: A key pathway that leads to necrosis is the failure of phagocytosis. What factors cause this?
  • Senescence driven inflammation: Cells undergo senescence within plaques, but they are thought to be inactive cells. We are investigating how senescent cells actively drive inflammation and plaque growth.

Keywords

phagocytosis ; cytokine/interleukin/chemokine receptors ; IL-1 ; protein purification ; immunosenescence ; cell culture ; interleukin ; cytokines ; aging ; scavenger receptors ; chemokines/monokines ; inflammation ; monocytes ; Toll-like receptors ; immunohistochemistry ; macrophages ; apoptosis ; human studies ; animal models ; recombinant protein expression ; pattern recognition receptors ; cytotoxicity ; necrosis ; microscopy ; fluorescence microscopy ; FACS ; Toll receptors

Topics

  • graft rejection
  • sterile inflammation
  • atherosclerosis
  • cardiac immunity

Key Publications

Zhang Y, Humphry M, Maguire JJ, Bennett MR, Clarke MCH: Intracellular IL-1 receptor 2 binding prevents cleavage and activity of IL-1α, controlling necrosis-induced sterile inflammation. Immunity. 2013; 38:2, 285.

Clarke MCH, Talib S, Figg N, Bennett MR: Vascular smooth muscle cell apoptosis induces IL-1-directed inflammation; effects of hyperlipidemia-mediated inhibition of phagocytosis. Circ Res. 2010; 106(2):363-72.

Clarke, MCH, Littlewood, TD, Figg, N, Maguire, JJ, Davenport, AP, Goddard, M, Bennett, MR. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis, and promotes calcification and medial degeneration. Circ Res. 2008; 102(12):1529-1538.

Clarke, MCH, Figg, N, Maguire, JJ, Davenport, AP, Goddard, M, Littlewood, TD, Bennett, MR. Apoptosis of vascular smooth muscle cells induces featu­res of plaque vulnerability in atherosclerosis. Nature Med. 2006; 12:1075-1080.

Clarke MCH, Savill J, Jones DB, Noble BS, Brown SB: Compartmentalised progenitor cell apoptosis generates functional platelets committed to caspase-independent death. J. Cell. Biol. 2003; 160(4): 577-87.

Clarke MCH, Brown SB, Magowan L, Sanderson H, Savill J: Constitutive death of platelets leading to scavenger receptor-mediated phagocytosis; a caspase-independent cell clearance program. J. Biol. Chem. 2000; 275: 5987-5996.