A5091475285- Tissue Engineering and Regenerative Medicine
- Congenital heart defects research
- Cardiac Fibrosis and Remodeling
- Cardiovascular Function and Risk Factors
- 3D Printing in Biomedical Research
- Cardiac electrophysiology and arrhythmias
- CRISPR and Genetic Engineering
- Signaling Pathways in Disease
- Mitochondrial Function and Pathology
- Cardiomyopathy and Myosin Studies
- Pluripotent Stem Cells Research
- ATP Synthase and ATPases Research
- Electrospun Nanofibers in Biomedical Applications
- Pancreatic function and diabetes
- RNA modifications and cancer
- Ion channel regulation and function
- Virus-based gene therapy research
- Viral Infections and Immunology Research
- Endoplasmic Reticulum Stress and Disease
- Autophagy in Disease and Therapy
- Protein Degradation and Inhibitors
- Hippo pathway signaling and YAP/TAZ
- Chemotherapy-induced cardiotoxicity and mitigation
- Kruppel-like factors research
- Fibroblast Growth Factor Research
University of Louisville
2019-2025
Baylor College of Medicine
2024-2025
Louisville Institute
2022-2023
University of Louisville Hospital
2020-2022
University of Manchester
2010-2016
Manchester Academic Health Science Centre
2011-2014
Preclinical testing of cardiotoxicity and efficacy novel heart failure therapies faces a major limitation: the lack an in situ culture system that emulates complexity human tissue maintains viability functionality for prolonged time. To develop reliable, easily reproducible, medium-throughput method to pig slices under physiological conditions period Here, we describe novel, biomimetic (300 µm thickness) 6 days culture. We optimized medium with continuous electrical stimulation at 1.2 Hz...
The regenerative capacity of the heart after myocardial infarction is limited. Our previous study showed that ectopic introduction 4 cell cycle factors (4F; CDK1 [cyclin-dependent kinase 1], CDK4 4], CCNB [cyclin B1], and CCND D1]) promotes cardiomyocyte proliferation in 15% to 20% infected cardiomyocytes vitro vivo improves cardiac function mice.
Identification of the signaling pathways that regulate cyclic nucleotide microdomains is essential to our understanding cardiac physiology and pathophysiology. Although there growing evidence plasma membrane Ca(2+)/calmodulin-dependent ATPase 4 (PMCA4) a regulator neuronal nitric-oxide synthase, physiological consequence this regulation unclear. We therefore tested hypothesis PMCA4 has key structural role in tethering synthase highly compartmentalized domain cell membrane. This functional...
Abstract The heart responds to pathological overload through myocyte hypertrophy. Here we show that this response is regulated by cardiac fibroblasts via a paracrine mechanism involving plasma membrane calcium ATPase 4 (PMCA4). Pmca4 deletion in mice, both systemically and specifically fibroblasts, reduces the hypertrophic pressure overload; however, knocking out cardiomyocytes does not produce effect. Mechanistically, lacking PMCA4 higher levels of secreted frizzled related protein 2...
The adult mammalian heart is recalcitrant to regeneration after injury, in part due the postmitotic nature of cardiomyocytes. Accumulating evidence suggests that cardiomyocyte proliferation fetal or neonatal mammals and regenerative non-mammalian models depends on a conducive metabolic state. Results from numerous studies hearts indicate conditions relatively low fatty acid oxidation, reactive oxygen species generation, high glycolysis are required for induction proliferation. Glycolysis...
Obesity-induced lipid overload in cardiomyocytes contributes to profound oxidative stress and cardiomyopathy, culminating heart failure. In this study, we investigate a novel mechanism whereby lipids accumulate cardiomyocytes, seek the relevant treatment strategies. P21-activated kinase 3 (PAK3) was elevated obese human myocardium, murine hearts upon diet- or fatty acid–induced stress, respectively. Mice with cardiac-specific overexpression of PAK3 were more susceptible development cardiac...
Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation incompletely understood. Here we show a robust pathway for new calcium signaling-based regenerative strategies. A drug screen targeting proteins involved cycling human embryonic stem cell-derived organoids (hCOs) revealed only the inhibition of...
BACKGROUND: Morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) is increased in metabolic disorders. However, options for preventing treating these prevalent outcomes are limited. Intramyocardial lipotoxicity contributes to cardiac dysfunction. Here, we investigate the mechanisms underlying endoplasmic reticulum degradation enhancing EDEM2 (endoplasmic degradation–enhancing alpha-mannosidase–like protein 2) regulation lipid homeostasis assess strategies that...
The coordinated gene and metabolic programs that facilitate cardiomyocyte entry progression in the cell cycle are poorly understood. purpose of this study was to identify changes influence myocyte proliferation.In adult mouse cardiomyocytes human induced pluripotent stem (hiPS-CMs), initiation by ectopic expression Cyclin B1, D1, CDK1, CDK4 (termed 4F) downregulated oxidative phosphorylation genes upregulated regulate ancillary biosynthetic pathways glucose metabolism. Results from analyses...
Abstract There is need for a reliable in vitro system that can accurately replicate the cardiac physiological environment drug testing. The limited availability of human heart tissue culture systems has led to inaccurate interpretations cardiac-related effects. Here, we developed c ardiac t issue ulture m odel (CTCM) electro-mechanically stimulate slices with stretches systole and diastole during cycle. After 12 days culture, this approach partially improved viability but did not completely...
Diabetes is a metabolic disorder with an increased risk of developing heart failure. Inflammation and damaged vasculature are the cardinal features diabetes-induced cardiac damage. Moreover, systemic stress triggers discordant intercellular communication, thus culminating in dysfunction. Fibroblast growth factor 21 (FGF21) pleiotropic hormone transducing cellular signals via fibroblast receptor 1 (FGFR1) its co-receptor beta-klotho (β-KL). This study first demonstrated decreased expression...
Myocardial inflammation contributes to cardiomyopathy in diabetic patients through incompletely defined underlying mechanisms. In both human and time-course experimental samples, hearts exhibited abnormal ER, with a maladaptive shift over time rodents. Furthermore, as cardiac ER dysfunction model, mice cardiac-specific p21-activated kinase 2 (PAK2) deletion heightened myocardial inflammatory response diabetes. Mechanistically, stress-induced CCAAT/enhancer-binding protein homologous (CHOP)...
Many novel drugs fail in clinical studies due to cardiotoxic side effects as the currently available vitro assays and vivo animal models poorly predict human cardiac liabilities, posing a multi-billion-dollar burden on pharmaceutical industry. Hence, there is worldwide unmet medical need for better approaches identify drug cardiotoxicity before undertaking costly time consuming 'first man' trials. Currently, only immature cells (human induced pluripotent stem cell-derived cardiomyocytes...
Abstract Aims Gene therapies to induce cardiomyocyte (CM) cell cycle re-entry have shown a potential treat subacute ischaemic heart failure (IHF) but not been tested in the more relevant setting of chronic IHF. Our group recently showed that polycistronic non-integrating lentivirus encoding Cdk1/CyclinB1 and Cdk4/CyclinD1 (TNNT2-4Fpolycistronic-NIL) is effective inducing CM ameliorating IHF models preventing subsequent IHF-induced congestions liver, kidneys, lungs rats pigs. Here, we aim...
Despite the development of clinical treatments, heart failure remains leading cause mortality. We observed that p21-activated kinase 3 (PAK3) was augmented in failing human and mouse hearts. Furthermore, mice with cardiac-specific PAK3 overexpression exhibited exacerbated pathological remodeling deteriorated cardiac function. Myocardium displayed hypertrophic growth, excessive fibrosis, aggravated apoptosis following isoprenaline stimulation as early two days. Mechanistically, using cultured...
Tumour necrosis factor-α (TNF-α) plays a key role in the regulation of cardiac contractility. Although cardiomyocytes are known to express TNF-α receptors (TNFRs), mechanism signal transmission is incompletely understood. The aim this study was investigate whether tumour suppressor Ras-association domain family protein 1 isoform A (RASSF1A) modulates signalling cardiomyocytes.We used RASSF1A knockout (RASSF1A(-/-)) mice and wild-type (WT) littermates study. Acute stimulation with low dose...
Abstract Background and Purpose Myocardial infarction (MI) is the leading cause of mortality globally due in part to limited ability cardiomyocytes (CMs) regenerate. Recently, we demonstrated that overexpression four‐cell cycle factors, CDK1, CDK4, cyclin B1 D1 (4F), induced cell division ~20% post‐mitotic CMs overexpressed 4F. The current study aims identify a small molecule augments 4F‐induced CM induction. Experimental Approach, Key Results Screening molecules with potential augment...
Many novel drugs fail in clinical studies due to cardiotoxic side effects as the currently available vitro assays and vivo animal models poorly predict human cardiac liabilities, posing a multi-billion-dollar burden on pharmaceutical industry. Hence, there is worldwide unmet medical need for better approaches identify drug cardiotoxicity before undertaking costly time consuming 'first man' trials. Currently, only immature cells (human induced pluripotent stem cell-derived cardiomyocytes...
Abstract The limited availability of human heart tissue and its complex cell composition are major limiting factors for reliable testing drug efficacy, toxicity understanding mechanism. Recently, we developed a functional pig slice biomimetic culture system that fully preserves the viability functionality 300 µm slices 6 days. Here, tested reliability this in delineating mechanisms known anti-cancer drugs cause cardiomyopathy. We three (doxorubicin, trastuzumab, sunitinib) associated with...