Stroke is the fourth leading cause of death and the leading cause of disability among Americans today. Due to the devastating effects of brain damage from stroke, there is an immediate need for better understanding the mechanisms and developing effective treatments. It has been well documented that blood-brain barrier (BBB, a dynamic cerebrovascular endothelial cell interface that maintains homeostasis in brain) disruption enhances vasogenic edema and further increases cytotoxic brain edema and is thought to promote hemorrhagic transformation in stroke. However, the time course of post-stroke BBB leakage, whether biphasic or progressive, remains debated. Understanding of when and how the post-stroke BBB is damaged, in relation to brain tissue injury is essential, as the efficacy of therapeutic interventions may rely on the knowledge of these mechanisms.It is well documented that cerebrovascular endothelial cells have a large volume of mitochondria compared with other endothelial cells or tissue types, suggesting the need for greater energy production. We have recently discovered that maintenance of mitochondrial energy production is critical to maintain the BBB integrity in an in vitro cerebrovascular endothelial cell culture model, an in vivo epidural application model, and an in vivo experimental stroke model. Another group has also demonstrated a mitochondrial mechanism that regulates BBB integrity and permeability using oxygen-glucose deprivation and reoxygenation (OGD-R), an in vitro model of ischemic reperfusion injury.MiRNAs are short non-coding functional RNAs that target certain messenger RNAs (mRNAs) based on sequence complementarity resulting in translational repression or site-specific cleavage. Our preliminary data showed the expression of miR34a in the serum is significantly increased by transient middle cerebral artery occlusion (tMCAO) in mice at early post-stroke reperfusion. Bioinformatics analysis predicts that miR-34a potentially targets and silences multiple mitochondria-associated mRNAs, which indicate miR-34a may play an important role in the regulation of mitochondrial energy production. Therefore, in this proposal, we hypothesize that miR-34a regulates BBB openings in stroke through mitochondrial mechanisms in cerebrovascular endothelial cells.
|Program type||Scientist Development Grant|
|Effective start/end date||07/01/2016 → 06/30/2019|