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:Environmental stressors present in the modern world can have a fundamental effect on the physiology and health of humans. Exposure to stressors like air pollution, heat and traffic noise has been linked to a pronounced increase in non-communicable diseases. Specifically, aircraft noise has been identified as a risk factor for cardiovascular and metabolic diseases, such as arteriosclerosis, heart failure, stroke and diabetes. Noise stress leads to neuronal activation with subsequent stress hormone release that ultimately leads to activation of the renin-angiotensin-aldosterone system, increasing inflammation and oxidative stress, with dramatic effects on the cardiovascular system. However, despite the epidemiological evidence of a link between noise stress and metabolic dysfunction, the consequences of exposure at the molecular, metabolic level of the cardiovascular system are largely unknown. Here we use a murine model system of aircraft noise exposure to show that noise stress profoundly alters heart metabolism. Within days of exposing animals to aircraft noise the heart has a reduced potential for utilising fatty-acid beta-oxidation, the tricarboxylic acid cycle, and the electron transport chain for generating ATP. This is compensated by shifting energy production towards glycolysis. Intriguingly, the metabolic shift is reminiscent of what is observed in failing and ischaemic hearts. Our results demonstrate that within a relatively short exposure time, the cardiovascular system undergoes a fundamental metabolic shift that bears the hallmarks of cardiovascular disease. Overall, aircraft noise induces rapid, detrimental metabolic shifts in the heart, resembling patterns seen in cardiovascular diseases. These findings underscore the urgent need to comprehend molecular consequences of environmental stressors, paving the way for targeted interventions aiming mitigating health risks associated with chronic noise exposure in our modern, noisy environments.
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.