MOURKIOTI
LAB
Research Interests
Skeletal muscle research: Disruption of skeletal muscle integrity results in muscle atrophy and degeneration but the cellular and molecular underpinnings that will promote regeneration remain elusive. We showed that inhibition of NF-κB pathway induces regeneration after injury and protects against denervation-induced muscle atrophy (Mourkioti et. al., JCI, 2006). Furthermore, our research revealed a muscle stem cell-autonomous increase in the activity of the p38 mitogen-activated protein kinase pathway (Cosgrove, et. al., Nature Medicine, 2014) and provided the first evidence that polarization of macrophages (from pro-inflammatory to anti-inflammatory) is fundamental for skeletal muscle regeneration in mice (Ruffel, Mourkioti, et. al., PNAs 2009). More recently, we developed a new mouse model (dystrophic mice with shorten telomeres, mdx/mTR mouse) that better replicates the phenotype of Duchenne Muscular Dystrophy, providing novel evidence that the skeletal muscle phenotype is caused by a failure of skeletal muscle stem cells to maintain the damage-repair cycle initiated by dystrophin deficiency (Sacco, Mourkioti, et. al., Cell, 2010).
Our lab has a long-term interest in understanding the fundamental aspects of skeletal muscle and cardiac function in normal or diseased conditions and in the practical aspects of manipulating these functions by using animal models and tissue engineering approaches for treatment intervention.
Cardiac research: Heart failure and myocardial infarction is the major source of morbidity and mortality in humans. Human hearts do not regenerate; instead damaged myocardium is replaced by fibrotic scar tissue. We previously uncovered critical roles of two molecular pathways that can be manipulated to improve cardiac damage: 1) cardiomyocyte-specific inhibition of the NF-κB pathway causes adult-onset dilated cardiomyopathy, which can be relieved with antioxidant treatment (Kratsios et. al., Circ. Res. 2010a) and 2) re-activating Notch signaling, using a clinical relevant protocol, which results in substantial improvement of cardiac function after myocardial damage (Kratsios et. al., Circ. Res. 2010b). Recently, we characterized the first dystrophic mouse with a spontaneous cardiac phenotype, supporting a link between telomere length and dystrophin deficiency in the etiology of DMD dilated cardiomyopathy and a murine model for testing therapeutic interventions (Mourkioti et. al., Nature Cell Biology, 2013).
We believe that combining bioengineering approaches with stem cell biology, testing cell-based therapies and modulating the signaling pathways of adult stem cells we can enhance the replacement of skeletal muscle and cardiac tissue upon injury. We are presently combining genetic knockout mice and gene recombination with cellular engineering techniques to investigate the temporal and spatial communication of cells and signaling pathways during muscle regeneration.