My main interest is to investigate the role of specific miRNAs in the metabolic abnormalities identified in pulmonary arterial hypertension (PAH), a rare but fatal disease characterised by profound vascular abnormalities in the peripheral arteries of the lung. Substantial changes in bioenergetics of pulmonary artery endothelial cells (PAECs) isolated from PAH patients, including reduced oxygen consumption of mitochondria and higher rates of glycolysis have been reported. This phenotype, a feature of cancer cells known as the Warburg effect, could provide new insights into the pathobiology of PAH and offer new therapeutic strategies. However, the mechanism responsible for these abnormalities has never been identified. My preliminary findings link these alterations with the down regulation of a specific miRNA, miR-124, a small, non-coding RNA able to negatively regulate gene expression by targeting specific messenger RNAs. miR-124 directly targets several enzymes involved in glycolysis. Therefore, the manipulation of this miRNA and the consequent restoration of normal glycolysis could represent a potential therapeutic approach in PAH.
The techniques used in this project include
This project if founded by British Heart Foundation. In 2013 I have been awarded with the first British heart Foundation immediate fellowship.
1. White K, Dempsie Y, Caruso P, Wallace E, McDonald RA, Stevens H, Hatley ME, Van Rooij E, Morrell NW, Maclean MR, Baker AH. Endothelial Apoptosis in Pulmonary Hypertension Is controlled by a microRNA/Programmed Cell Death 4/Caspase-3 Axis. Hypertension. 2014 Apr 14.
2. Lavoie JR, Ormiston ML, Perez-Iratxeta C, Courtman DW, Jiang B, Ferrer E, Caruso P, Southwood M, Foster WS, Morrell NW, Stewart DJ. Proteomic analysis implicates translationally controlled tumor protein as a novel mediator of occlusive vascular remodeling in pulmonary arterial hypertension. Circulation. 2014 May 27;129(21):2125-35.
3. Toshner M, Dunmore BJ, McKinney EF, Southwood M, Caruso P, Upton PD, Waters JP, Ormiston ML, Skepper JN, Nash G, Rana AA, Morrell NW. Transcript analysis reveals a specific HOX signature associated with positional identity of human endothelial cells. PLoS One. 2014 Mar 20;9(3):e91334.
4. Caruso P, Dempsie Y, Stevens H, McDonald R, Long. L, Lu R, White K, Mair K, Southwood M, Upton PD, Xin M, van Rooij E, Olson E, Morrell NW, MacLean MR and Baker AH. A role for microRNA-145 in the development of pulmonary arterial hypertension: Evidence from mouse models and patient samples. Circ Res. Jun 19 2012.
5. Morecroft I, White K, Caruso P, Nilsen M, Loughlin L, Alba R, Reynolds PN, Danilov SM, Baker AH. and MacLean MR. Gene therapy by targeted adenovirus-mediated knockdown of pulmonary endothelial Tph1 attenuates hypoxia-induced pulmonary hypertension. Mol Ther. 2012 Aug;20(8):1516-28.
6. Cherubini G, Naim V, Caruso P, Burla R, Bogliolo M, Cundari E, Benihoud K, Saggio I and Rosselli F. The FANC pathway is activated by adenovirus infection and promotes viral replication-dependent recombination. Nucleic Acids Res. 2011 Jul;39(13):5459-73.
7. Caruso P, MacLean MR, Khanin R, McClure J, Soon E, Southwood M, McDonald RA, Greig JA, Robertson KE, Masson R, Denby L, Dempsie Y, Long L, Morrell NW. and Baker AH. Dynamic changes in lung miRNA profiles during the development of pulmonary hypertension due to chronic hypoxia and monocrotaline. Arteriosclerosis, Thrombosis, and Vascular Biology, 2010 Apr;30(4):716-23.
8. Caruso P, Burla R, Piersanti S, Cherubini G, Remoli C, Martina Y, Saggio I. Prion expression is activated by Adenovirus 5 infection and affects the adenoviral cycle in human cells. Virology. 2009 Mar 15;385(2):343-50.