Project description:The transcatheter aortic valve replacement (TAVR) procedure has emerged as a minimally invasive treatment for patients with aortic valve stenosis (AVS). However, alterations in serum factor composition and biological activity after TAVR remain unknown. Here, we quantified the systemic inflammatory effects of the TAVR procedure and hypothesized that alterations in serum factor composition would modulate valve and cardiac fibrosis. Serum samples were obtained from patients with AVS immediately before their TAVR procedure (pre-TAVR) and about one month afterwards (post-TAVR). Aptamer-based proteomic profiling revealed alterations in post-TAVR serum composition, and ontological analysis identified inflammatory macrophage factors implicated in myofibroblast activation and deactivation. Hydrogel biomaterials used as valve matrix mimics demonstrated that post-TAVR serum reduced myofibroblast activation of valvular interstitial cells relative to pre-TAVR serum from the same patient. Transcriptomics and curated network analysis revealed a shift in myofibroblast phenotype from pre-TAVR to post-TAVR and identified p38 MAPK signaling as one pathway involved in pre-TAVR-mediated myofibroblast activation. Post-TAVR serum deactivated valve and cardiac myofibroblasts initially exposed to pre-TAVR serum to a quiescent fibroblast phenotype. Our in vitro deactivation data correlated with patient echocardiography data and multi-morbidity scores, and correlations were dependent upon hydrogel stiffness. Sex differences in cellular responses to male and female sera were also observed and may corroborate clinical observations regarding sex-specific TAVR outcomes. Together, our observations support the hypothesis that alterations in serum composition after a TAVR procedure may promote an anti-fibrotic fibroblast phenotype.
Project description:The randomized, dose-response PHITE (Precision High-Intensity Training Through Epigenetics) clinical trial used molecular and phenomic profiling to compare responses to traditional (TRAD) endurance -plus resistance training (TRAD) and high-intensity tactical training (HITT). Serum exosomal-derived microRNAs were profiled from 90 individuals throughout a 12-week traditional (TRAD) or high-intensity tactical training (HITT) intervention and after a subsequent 4-week detraining period. miRNA data and associated molecular and phenomic profiling was used to (1) assess the affects of TRAD and HITT on physiological performance and body composition, (2) assess the integrated biocircuitry driving exercise adaptations and response heterogeneity and (3) define the effects of early-phase detraining.
Project description:This study investigated how serum composition modulates ACTH-induced gene expression in primary rat adrenocortical cells. Cells were cultured in standard or charcoal-stripped serum (which removes steroids along with other serum components such as growth factors and lipids), then stimulated with ACTH (10 nM) for 24 hours. Microarray analysis revealed that ACTH under serum-depleted conditions activated 532 differentially expressed genes (456 upregulated, 76 downregulated), compared to only 220 genes under standard conditions. Key steroidogenic genes including Cyp11a1, Cyp11b1, Star, and Scarb1 showed markedly enhanced upregulation in the serum-depleted condition. Functional enrichment analysis demonstrated that ACTH preferentially activated steroid biosynthesis and lipid metabolic pathways while suppressing cell cycle and extracellular matrix-related genes, particularly under serum depletion. These findings demonstrate that serum composition critically shapes ACTH responsiveness, revealing multifactorial regulation of adrenocortical cell function beyond steroid feedback alone.
Project description:Proteomics of thyroid tumours - Proteomics of thyroid tumours provides new insights into their molecular composition and changes associated with malignancy