Project description:Cardiac maturation is an important developmental phase where there are profound biological and functional changes after birth in mammals. Herein, we use our profiling of human heart maturation in vivo to identify key drivers of maturation in our human cardiac organoid (hCO) model. In this dataset, we exemplified the applicability of our mature organoids in modelling cardiovascular disease. Pathogenesis of Desmoplakin (DSP) cardiomyopathies are driven by complex cellular interplay and changes in excitation-contraction coupling. A patient (MCHTB11), was screened against a 202 cardiac gene panel for clinically-relevant rare DNA variants (frequency < 0.04%). A homozygous 2 bp deletion was identified in the DSP gene, and recapitulated in our hCOs utilising CRISPR. In this screen, we also utilised INCB054329, a bromodomain extra-terminal inhibitor, to suppress diastolic dysfunction induced by the DSP mutant. In this dataset, we evaluate the proteomic remodelling induced by DSP-mutants (DSP) versus recovered mutants (CTRL), with and without INCB (n=3-4 for each group).
Project description:Microgravity and prolonged periods of inactivity cause a variety of diseases, including skeletal muscle mass loss and weakening as well as cardiovascular deconditioning. The primary causes of the inadequate preventative measures for these deconditionings are the lack of biomarkers and unknown underlying mechanisms of cardiovascular and skeletal muscle deconditioning in these conditions. Here, we used a hindlimb unloading (HU) mouse model that replicates astronauts in space and bedridden patients to first evaluate cardiovascular and skeletal muscle performance. Serum samples from these mice were used to identify new biomarkers using metabolomic and proteomic approaches. Three weeks of unloading resulted in alterations in cardiovascular system function in C57/Bl6 mice, as measured by changes in mean arterial pressure and heart weight. Unloading for three weeks also altered skeletal muscle function, resulting in a decrease of grip strength in HU mice, as well as skeletal muscle atrophy, as shown by a drop in muscle mass. A two-week recovery time from the unloading condition partially reversed these alterations, stressing the importance of the recovery process.
Project description:We used transverse aortic constraction pressure overload hypertrophy mouse hearts as a model of cardiovascular disease to study the genetic changes between TAC and SHAM (normal) mouse hearts and over 1 circadian cycle (24h). This is one approach to identify diurnal genetic biomarkers of cardiovascular disease. The micorarray approach allowed to see the gene expression in all genes in cardiovascular disease and sham hearts. There are 36 samples of cardiovascular disease (TAC) and normal SHAM hearts. For TAC: There were 3 mice sacrificed at each time point as biological replicates, for 6 timepoints over 24 hrs. For SHAM: There were 3 mice sacrificed at each time point as biological replicates, for 6 timepoints over 24 hrs.
Project description:We used transverse aortic constraction pressure overload hypertrophy mouse hearts as a model of cardiovascular disease to study the genetic changes between TAC and SHAM (normal) mouse hearts and over 1 circadian cycle (24h). This is one approach to identify diurnal genetic biomarkers of cardiovascular disease. The micorarray approach allowed to see the gene expression in all genes in cardiovascular disease and sham hearts.
Project description:Uremic cardiomyopathy is a clinically highly relevant cause of cardiovascular events in patients with chronic kidney disease (CKD). This study aimed at a comprehensive analysis of cardiac function and cardiac pathological characteristics in adenine-induced CKD in 129/Sv mice. This included the analysis of kidney function and morphology, heart function as well as cardiac hypertrophy, fibrosis and calcification. Also, cardiac RNA-sequencing was performed. Although overall, no cardiac dysfunction, hypertrophy or fibrosis could be observed, prolonged moderate CKD in this mouse model enhanced cardiac oxidative stress markers. In line, cardiac RNA-sequencing revealed an increase in oxidative stress-inducing signaling in CKD as well as anti-inflammatory feedback responses. This suggests a maladaptive preconditioning of the heart in CKD, which could increase the risk of enhanced cardiovascular damage upon additional cardiovascular risk factors and/or events.
Project description:Background: We have found that extracellular vesicles (EV) secreted by embryonic stem cell-derived cardiovascular progenitor cells (hES-CPg) recapitulate the therapeutic effects of these cells in a model of chronic heart failure (CHF). Objectives: Our goal was to test other cellular sources of EV and to explore their mechanism of action.