Heat shock proteins in brain ischemia and stroke

Veterans Affairs Med Ctr San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by applicant): Stroke is a common affliction among veterans, and treatments are few. Brain ischemia frequently causes disruption of the blood brain barrier (BBB) leading to brain edema and hemorrhage which can complicate an already catastrophic illness. Recent work in the field has implicated matrix metalloproteinases (MMPs), a family of Zn-dependent endopeptidases, in the breakdown of the extracellular matrix and BBB leading to brain edema and hemorrhage. Work by our labs and those of our collaborators' have focused on the protective potential of heat shock proteins, namely, the highly inducible 70 kD heat shock protein (HSP70). HSP70 appears to have cytoprotective properties by nature of its chaperone functions, presumably leading to enhancement of nascent protein folding and prevention of protein aggregation. However, work in related fields has shown that HSPs may also be involved in the expression and processing of MMPs. We recently showed that overexpression of HSP70 or its induction by heat stress reduced expression of MMPs in cultured astrocytes at the transcriptional and translational level. In addition to preventing MMP transcription and translation, we have preliminarily found that HSP70 can also prevent processing of pro-MMPs to their active form, suggesting an additional action of protection. In this application, we propose to further explore these observations that HSP70 protects the brain against stroke by preventing BBB disruption, edema and hemorrhage by inhibiting the expression, translation and processing of MMPs. Aim 1 will use cell cultures of brain derived endothelial cells and astrocytes to establish which cell types generate HSP70 and MMPs following various stimuli, and if HSP70 can prevent disruption of the BBB using in vitro models. Aim 2 will determine how HSP70 interacts with MMPs. HSP70 mutants lacking either functional ATPase or substrate binding domains will be studied. Aim 3 will explore the significance of HSPs on BBB integrity, brain edema/hemorrhage and MMPs will be studied using in vivo models of experimental stroke.