The structural and functional abnormalities in the cerebral endothelium during cerebral ischemia are well- known to affect the extent of ischemic brain injury and neurological outcomes. Therefore, the brain endothelium becomes an important therapeutic target for the inhibition of cerebrovascular dysfunction in ischemic stroke. However, the regulatory mechanisms of cerebral endothelial dysfunction after cerebral ischemia remain largely unexplored. Previously we have documented the important regulatory roles of microRNAs in the cerebral vasculature, in particular the cerebral vascular endothelium. However, the functional significance and molecular mechanisms of other classes of non-coding RNAs in the regulation of cerebrovascular endothelial pathophysiology after ischemic stroke are completely unknown. Using RNA-sequencing technology, we profiled long non-coding RNAs (lncRNAs) expressional signatures in primary brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD). After 16h of OGD exposure, the expression levels for 362 of the 10,677 lncRNAs analyzed changed significantly, including a total of 147 lncRNAs increased and 70 lncRNAs decreased by more than 2-fold. Interestingly, metastasis associated lung adenocarcinoma transcript 1 (Malat1) is one of the most highly upregulated OGD-responsive endothelial lncRNAs, which has been initially discovered as a tumor-associated lncRNA involved in epigenetic control of gene expression. Furthermore, we found that loss-of-Malat1 function significantly increased OGD- induced loss of endothelial marker and endothelial inflammation in BMECs. In this exploratory proposal, we will test our central hypothesis that Malat1 plays a critical role in protecting the cerebral microvasculature from cerebral ischemic insults by inhibiting endothelial degeneration and inflammation. We propose to test this hypothesis with the following two aims:
Aim 1 is to define the pathological profiles of Malat1 in cerebrovascular endothelium after ischemic stroke.
Aim 2 is to identify the functional role of Malat1 in regulating ischemic cerebrovascular and brain damage. The broad, long-term goal is to understand the essential role of lncRNAs in cerebrovascular pathologies after ischemic stroke and to develop potential lncRNA-based therapies/ intervention for ischemic stroke.
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 long non-coding RNAs (lncRNAs) play a critical role in protecting the cerebral microvasculature from cerebral ischemic insults by inhibition of endothelial degeneration and inflammation. The successful implementation of this exploratory proposal will lead us to discover novel cerebral endothelial regulators and may reveal new lncRNA-based approaches for therapeutic intervention in cerebrovascular diseases such as stroke.
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