Stroke is a major cause of death and disability in the US. Unfortunately, current therapeutic options are seriously limited. Emerging evidence shows that post-ischemia angiogenesis plays a crucial role in the recovery of blood flow and neuronal metabolism after stroke. Thus, promoting angiogenesis via various approaches appears as a promising treatment for experimental ischemic stroke. MicroRNAs (miRs) function as a novel class of noncoding small RNAs that negatively modulate protein expression. MiRs have been implicated in a variety of human neurological diseases. Recent studies have revealed important roles for miRs in regulating angiogenesis. We and others have shown the involvement of miRs in the pathogenesis of ischemic brain injury, suggesting miRs as potential therapeutic targets in stroke. However, the functional significance and mechanisms of miR molecules in the regulation of angiogenic processes after stroke are poorly understood. The miR-15a/16-1 cluster is the first identified miR group associated with human carcinogenesis. Recently, dysregulated plasma miR-15a/16-1 levels are found in stroke patients, showing great potential as diagnostic and prognostic biomarkers. Inhibition of miR-15 has been shown to protect against myocardial infarction (MI). Thus, several pharmaceutical companies (MiRagen therapeutics; Servier) consider miR-15 as an important miR target to develop miR-based drugs for improving post-MI recovery. We reported for the first time that endothelial miR-15a can significantly suppress cell-autonomous angiogenesis in hindlimb ischemia. Moreover, our preliminary studies showed that the levels of the miR-15a/16-1 cluster are significantly increased in the cerebral vasculature at the penumbral area 7d after middle cerebral artery occlusion (MCAO) in mice. Of note, EC-selective miR-15a/16-1 transgenic overexpression leads to reduced cerebral microvessels and increased brain infarction in mice 7d after MCAO. Furthermore, we found that the miR-15a/16-1 cluster can bind to the 3'-UTR of vascular endothelial growth factor (VEGF) mRNA and inhibit its protein expression. These findings prompt the central hypothesis that the miR-15a/16-1 cluster functions as a critical regulator in post-ischemic cerebral angiogenesis, thus affecting long-term neurological outcomes after ischemic stroke.
Three aims will be performed in this proposal.
Aim 1 : Determine the functional role of the miR-15a/16-1 cluster in regulating post-stroke angiogenesis;
Aim 2 : Identify the molecular targets of the miR- 15a/16-1 cluster in regulating post-stroke angiogenesis;
Aim 3 : Determine whether miR-15a/16-1-mediated angiogenesis affects long-term stroke outcomes.
Stroke is the fourth most common cause of death and the leading cause of adult disability in the United States. Currently, acute therapeutic interventions are limited to thrombolytic therapy within a narrow time window and development of effective therapies is urgently required. The object of this application is to test our hypothesis that the miR-15a/16-1 cluster functions as a critical regulator in cerebral angiogenesis and affects long-term neurological outcomes after ischemic stroke. The successful implementation of this proposal will elucidate the functional importance of miR-15a/16-1-mediated post-stroke angiogenesis and may eventually lead us to discover novel pharmaceutical targets to mediate angiogenesis with promise for further development of neurorestorative therapies after ischemic stroke.
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