This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator.
Aims and Results Thrombolytic therapy with tissue plasminogen activator (tPA), the only FDA-approved treatment for acute ischemic stroke, is constrained to 5% ischemic stroke patients largely due to the increased (10-fold) risk of symptomatic hemorrhagic transformation (HT). Severe ischemic damage to the blood brain barrier (BBB) has been considered as the prerequisite for the occurrence of HT. However, several key questions remain outstanding about the causal link between BBB damage and HT. For example, how does the degree of BBB damage correlate to the severity of HT? Is there a threshold of BBB damage, particularly at early-stage of stroke, which portends subsequent HT? What are the mechanisms leading to early severe BBB damage? We have recently developed magnetic resonance imaging (MRI) technique to noninvasively and quantitatively measure BBB damage in rats by assessing the influx rate of gadolinium-diethylene-triamine penta-acetic acid (Gd-DTPA) from blood to the brain. This technical advance would allow us to correlate early BBB damage to subsequent HT following tPA treatment. In addition, the obtained MRI permeability map will also define specific regions with severe BBB damage at early-stage of stroke, and thus guide us to explore the underlying molecular mechanisms for this severe early damage. Our previous work has shown that matrix metalloproteases (MMPs), in particular MMP-2/9, are increased in the ischemic brain and contribute to BBB disruption by degrading tight junction protein occludin and claudin-5, and tPA may induce HT via augmenting ischemia-induced MMP-9 up-regulation. As a fact, these studies have focused on the subacute changes of MMP-2/9, and little has been studied about their changes and roles in BBB damage at hyperacute stage (within the first few hours after stroke onset), when de novo synthesis is not likely responsible for the increase of MMP-2/9 because it takes time for them to be transcribed and translated in affected brain cells. In this project, we propose to study early BBB disruption and its relation to hemorrhagic transformation in ischemic stroke. The project will utilize state of the art technology available in UNM BRaIN center to study BBB damage and the underlying molecular mechanisms using in vivo ischemic stroke model (middle cerebral artery occlusion, MCAO) and in vitro ischemic model (oxygen glucose deprivation, OGD). Our approaches include MRI, two-photon microscopy, fluorescence microscopy, and other cellular and molecular techniques.
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