Stroke is a major public health problem and is a leading cause of serious, long-term disability in the US and worldwide. Significant scientific effort is focused on the strategies to enhance angiogenesis after cerebral ischemia, which may improve clinical outcomes during post-stroke recovery. Endothelial morphogenesis is an essential component of vascular remodeling, involving complex interactions between genes and signaling molecules. microRNAs (miRNAs), short mRNA-interfering molecules, control post-transcriptional gene expression in many tissues, including vasculature. miRNA dysregulation has been recently associated with numerous human diseases;therefore, modulation of miRNA expression may offer a significant therapeutic potential. Our objective and long-term goal is to employ regulation of vascular miRNA expression as a therapeutic method for stroke treatment. The central hypothesis is that in vivo inhibition of specific miRNAs will support revascularization and thus, brain recovery following stroke. This hypothesis is based on our published and preliminary studies suggesting that three specific miRNAs, miR-155, miR-100 and miR-let-7i, could coordinate a revascularization process. The rationale for the proposed research is that once we determine the role of miR-155, miR-100 and miR-let-7i in post-stroke angiogenesis, we can support this process through modulation of miRNA activity in vivo. To test the central hypothesis, we propose the following Aims: 1) To study the effect of specific miRNAs on the in vitro endothelial proliferation, invasion, migration and overall capillary-forming ability. 2) To study the influence of the in vivo inhibition of specific miRNAs on post-stroke revascularization. 3) To assess whether pro-angiogenic effect of specific miRNA inhibition correlates with the improved recovery after stroke. We believe that the proposed research is innovative because it offers a new approach to post-stroke recovery: the direct regulation of post-ischemic angiogenesis through modulation of specific miRNA expression. We believe that the proposed research is significant because it is expected to lead to the development of novel therapeutic strategies for improving the post-ischemic recovery.
The project is expected to trigger the development of novel strategies aiming to improve recovery following stroke. We intend to enhance revascularization of the damaged brain tissue through direct regulation of specific microRNA activity, in order to support regeneration following experimental ischemia in mice. It is our belief, that in vivo microRNA inhibition could potentially be used as a post-ischemic treatment. The proposed project is relevant to public health, and thus, to the NIH mission, which is to apply the scientifi knowledge to enhance health and reduce the burdens of illness and disability.
|Pena-Philippides, Juan Carlos; Caballero-Garrido, Ernesto; Lordkipanidze, Tamar et al. (2016) In vivo inhibition of miR-155 significantly alters post-stroke inflammatory response. J Neuroinflammation 13:287|
|Caballero-Garrido, Ernesto; Pena-Philippides, Juan Carlos; Lordkipanidze, Tamar et al. (2015) In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke. J Neurosci 35:12446-64|