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Anti-apoptotic cFLIP proteins in cerebro-vascular injury

The cFLIP proteins are endogenous cytoplasmic factors that inhibit apoptosis and promote survival in many cell types, including vascular smooth muscle and endothelial cells. These native cell-protective agents are also involved in the downstream integration of angiogenic signals (e.g. VEGF, bFGF). No study has been made of the role of cFLIP in cerebrovascular disorders such as stroke. Dr Hainsworth is a Cellular Neuroscientist and was one of the first investigators to report changes in cFLIP expression in rodent and human brain in injury states (traumatic injury, dementia). This project will investigate whether cFLIP proteins are involved in vascular injuries in a non-surgical in vivo model of stroke.

We will determine the changes in cFLIP expression around areas of cerebrovascular injury, and the cell types involved (neurones, endothelial, astrocytes, etc). Using a proteomic approach we will compare cFLIP binding partners in lesioned areas versusuninjured brain, as a clue to possible functions of cFLIP. Areas of injury will be identified in vivo by MR imaging and subsequently confirmed histologically.

Fig 1. Cerebral cortex following traumatic injury; green = cFLIP, red = GFAP (reactive astrocytes), yellow = overlap. From Hainsworth et al 2005.

References

Irmler M, Thome M, Hahne M et al. Inhibition of death receptor signals by cellular FLIP. Nature. 1997; 388:190-195.

Martin-Villalba A, Herr I, Jeremias I et al. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J Neurosci. 1999; 19:3809-3817.

Hainsworth AH, Bermpohl D, Webb TE et al. Expression of cellular FLICE inhibitory proteins (cFLIP) in normal and traumatic murine and human cerebral cortex. J Cereb Blood Flow Metab. 2005; 25:1030-1040.

Matsumori Y, Northington FJ, Hong SM et al. Reduction of caspase-8 and -9 cleavage is associated with increased c-FLIP and increased binding of Apaf-1 and Hsp70 after neonatal hypoxic/ischemic injury in mice overexpressing Hsp70. Stroke. 2006; 37:507-512.