Vascular targeting of an atypical surface translocated αB-crystallin for the treatment of irradiated brain arteriovenous malformations.

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Abstract AVBS 2019
Vascular targeting of an atypical surface-translocated αB-crystallin for the treatment of irradiated brain arteriovenous malformations
Lucinda S. McRobb1, Sinduja Subramanian1, Matthew J. McKay2, Mark P. Molloy2,3 and Marcus A. Stoodley1
1Department of Clinical Medicine, Macquarie University, Sydney, Australia, 2Australian Proteome Analysis Facility, Macquarie University, Sydney, Australia, 3Kolling Institute, Northern Clinical School, University of Sydney, Sydney, Australia.
Brain arteriovenous malformations (bAVMs) are tangled collections of abnormal blood vessels that are a significant cause of haemorrhagic stroke, neurological disability or death. Almost one third are untreatable using current methods. We aim to use stereotactic radiosurgery to prime novel protein expression on the surface of bAVM vessels for antibody-directed delivery of thrombotic agents, to induce rapid thrombosis and closure. Examination of the endothelial surface proteome identified a putative radiation-stimulated biomarker as αB-crystallin (CRYAB), a small heat shock protein that normally acts as an intracellular chaperone to misfolded proteins. This study aimed to validate and characterise the unusual association of this target with the luminal surface and pre-test pro-thrombotic CRYAB-targeting conjugates for radiation-directed thrombosis.
Immunostaining of cultured brain endothelial cells and rat-model AVM tissue confirmed de novo induction of CRYAB in response to radiation (20 Gy). Western analysis of whole cell lysates revealed significant induction of the intracellular CRYAB monomer (20 kDa) however this was completely absent from the cell-surface fraction enriched by biotin-labelling and streptavidin pull-down. Contrastingly, a 65 kD immuno-positive band was consistently observed at the apical surface, but only after irradiation, suggesting radiation induces translocation of an atypical CRYAB-positive isoform to the endothelial surface. To assess targeting potential under high laminar flow, a thrombin and anti-CRYAB antibody conjugate was tested in an in vitro parallel-plate flow system containing human whole blood. The observed radiation-specific binding and thrombi formation suggests that further in vivo characterisation of CRYAB as a radiation biomarker for vascular targeting in bAVMs is warranted.


ConferenceInaugural Joint Scientific Meeting of AVBS/ANZMS/AAVBM
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