PROJECT SUMMARY
lschemic stroke is the major type of stroke with high mortality and morbidity, and the health care costs are
exorbitant and result in a significant societal burden. Currently although limited therapies including
thrombolysis and endovascular clot removal have been approved for the treatment of acute ischemic brain
injury, many patients still die or remain disabled. Underlying mechanisms remain poorly understood, hindering
the development of effective and specific treatments for this health concern. Thus, there is an urgent need to
further investigate the molecular mechanisms and identify effective therapeutic targets. Neuroinflammation is a
critical contributor to the pathophysiology of acute ischemic brain injury, in which microglial activation plays a
central role. We have recently discovered that microRNA210 (miR210) inhibition significantly reduced brain
microglial activation and inflammatory response post-stroke in mice. Our preliminary data also showed miR210
mimic transfection upregulated pro-inflammatory cytokine in primary microglia, and miR210 inhibition reduced
the expression of pro-inflammatory cytokine IL-1 f3 after oxygen-glucose deprivation (OGD). These findings
suggest a new mechanism of miR210 in microglial inflammatory response contributing to ischemic brain injury.
The mitochondria are a major target of miR210 during hypoxia and reprogramming of mitochondrial
metabolic switch from oxidative phosphorylation to glycolysis contributes to pro-inflammatory microglial
activation. We and others have demonstrated that miR210 reduces mitochondrial oxidative phosphorylation by
negatively regulating a number of electron transport chain (ETC)-related genes in multiple cells and increases
mitochondrial dysfunction. However, whether miR210 promotes metabolic shift in hypoxic mitochondrial
respiration in favor of glycolysis and drives pro-inflammatory microglial response in the setting of stroke is
unknown and requires further investigation. Thus, this proposal will attempt to reveal the mechanistic links of
metabolic reprogramming in miR210-mediated pro-inflammatory microglial activation in ischemic brain injury.
We will evaluate the mechanism of miR210-mediated mitochondrial metabolic shift in programming of proinflammatory
microglia and neurotoxicity. We will also determine whether and to what extent miR210
deficiency inhibits microglial mitochondrial dysfunction and reduces neuroinflammation after acute ischemic
brain injury. We expect to generate unique insights into the novel role of epigenetic mechanism in the
activation of microglial pro-inflammatory phenotype through metabolic shift in the brain post-stroke. The
outcome of this study will delineate the mechanism of miR210 in driving microglial inflammatory response. It
represents a major breakthrough and paradigm-shifting focus of research and will provide new visions into a
novel target of miR210 in potential therapeutic strategies for acute ischemic brain injury.