The most feared, unpredictable complication of thoracic-abdominal aortic aneurysm (TAAA) repair surgery is paraplegia caused by ischemic injury to the spinal cord (SC). There is urgency to identify new molecules that would complement existent, non-pharmacological preventive strategies. With this aim, we have developed a mouse model of TAAA where aortic cross-clamping (ACC) results in the development of central cord edema, gray matter damage, and delayed hind-limb paralysis. MicroRNA 155 (miR-155), a short non-coding RNA that negatively regulates the expression of a number of target transcripts, has been involved in pathologies such as chronic inflammation and cancer. Using our mouse model, we have found that miR-155 expression increases in motoneurons and endothelial cells of the SC following ACC. In addition, we have established that the ablation of the miR-155 gene limits the development of central cord edema, reduces the extent extend of SC gray matter damage, and decreases the rate of paralysis by 40%. We further found that, in ischemic SC, miR-155 targets Mfsd2a transcripts directly. Mfsd2a encodes a transporter in charge of supplying neurons with the indispensable omega-3 polyunsaturated docosahexaenoic (DHA) acid. Mfsd2a is also critical for the maintenance of the integrity of blood-brain barrier. These data suggest that miR-155 might target a number of transcripts and have compounding deleterious effects in the different compartments of the neurovascular unit. Therefore, we propose two complementary approaches to analyze miR-155 specific effects in endothelial cells and motoneurons. First, we will analyze the consequences on edema development, gray matter damage and paralysis of specifically deleting miR-155 in endothelial cells or motoneurons in our mouse ACC model. Secondly, mice that specifically overexpress miR-155 in either endothelial cells or motoneurons will be used for transcriptome analyses in order to identify miR-155 critical targets in these two cell compartments in normal, non ischemic conditions. At the end of this study, we anticipate to have identified the most critical targets of miR-155 in endothelial cells and motoneurons. These data will help to design new drugs aimed at combining the normalization of the expression of miR-155 and of its critical target transcripts in ischemic SC. Given that microRNA-directed therapies are now on clinical trials, we believe that our study holds great translational potentials not only for the prevention of paraplegia after TAAA repair surgery, but also for the treatment of neuronal ischemia due to stroke or SC/brain traumatic injuries where deleterious effects of miR-155 take place.
Paraplegia (paralysis affecting the legs) is one of the most feared and devastating complication of thoracic- abdominal aortic aneurysm repair surgery that still remains unpredictable. Unfortunately, there is yet no pharmacological preventive strategy to protect against paraplegia, therefore it is critical to improve our understanding of its pathophysiology to identify targets for the development of new drugs. This study is aimed at identifying the key targets of miR-155, a regulatory gene whose expression increases in motor neurons and endothelial cells when spinal cord damage occurs, using a mouse model of delayed hind-limb paralysis that already allowed us to demonstrate that impairing miR-155 activity decreases the risk to develop paralysis.
| Awad, Hamdy; Bratasz, Anna; Nuovo, Gerard et al. (2018) MiR-155 deletion reduces ischemia-induced paralysis in an aortic aneurysm repair mouse model: Utility of immunohistochemistry and histopathology in understanding etiology of spinal cord paralysis. Ann Diagn Pathol 36:12-20 |
| Tili, Esmerina; Michaille, Jean-Jacques; Piurowski, Victoria et al. (2017) MicroRNAs in intestinal barrier function, inflammatory bowel disease and related cancers-their effects and therapeutic potentials. Curr Opin Pharmacol 37:142-150 |
| Awad, Hamdy; Ramadan, Mohamed Ehab; El Sayed, Hosam F et al. (2017) Spinal cord injury after thoracic endovascular aortic aneurysm repair. Can J Anaesth 64:1218-1235 |
