A5034717131- Connexins and lens biology
- Cardiac electrophysiology and arrhythmias
- Ion channel regulation and function
- Cardiomyopathy and Myosin Studies
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Cardiovascular Effects of Exercise
- Heat shock proteins research
- Viral Infections and Immunology Research
- Nicotinic Acetylcholine Receptors Study
- Mitochondrial Function and Pathology
- Neuroscience and Neuropharmacology Research
- Adipokines, Inflammation, and Metabolic Diseases
- Viral Infections and Vectors
- Cancer-related molecular mechanisms research
- Cardiac Fibrosis and Remodeling
- Neuroscience and Neural Engineering
- Mosquito-borne diseases and control
- Barrier Structure and Function Studies
- Integrated Circuits and Semiconductor Failure Analysis
- RNA Interference and Gene Delivery
- Advanced Breast Cancer Therapies
- Metastasis and carcinoma case studies
- Cancer Cells and Metastasis
Virginia Tech
2016-2025
Biomedical Research Institute
2019-2025
Carilion Roanoke Memorial Hospital
2016-2025
Carilion Clinic
2016-2025
St. James's Hospital
2024
The University of Queensland
2024
Virginia State University
2019
NHS Ayrshire and Arran
2018
University Hospital Ayr
2018
Cedars-Sinai Medical Center
2013-2014
Estrogen, progesterone, and HER2 receptor-negative triple-negative breast cancers encompass the most clinically challenging subtype for which targeted therapeutics are lacking. We find that tumors exhibit elevated MYC expression, as well altered expression of regulatory genes, resulting in increased activity pathway. In primary tumors, signaling did not predict response to neoadjuvant chemotherapy but was associated with poor prognosis. exploit found by using a synthetic-lethal approach...
In cancer progression, carcinoma cells gain invasive behavior through a loss of epithelial characteristics and acquisition mesenchymal properties, process that can lead to epithelial-mesenchymal transition (EMT). TGF-β is potent inducer EMT, increased signaling in thought drive cancer-associated EMT. Here, we examine the physiological requirement for mTOR complex 2 (mTORC2) undergoing rapidly induces mTORC2 kinase activity controls cell progression By regulating EMT-associated cytoskeletal...
Gap junctions form electrical conduits between adjacent myocardial cells, permitting rapid spatial passage of the excitation current essential to each heartbeat. Arrhythmogenic decreases in gap junction coupling are a characteristic stressed, failing, and aging myocardium, but mechanisms decreased poorly understood. We previously found that microtubules bearing hemichannels (connexons) can deliver their cargo directly adherens junctions. The specificity this delivery requires microtubule...
Background— Heart disease is a leading cause of mortality throughout the world. Tissue damage from vascular occlusive events results in replacement contractile myocardium by nonfunctional scar tissue. The potential new technologies to regenerate damaged significant, although cell-based therapies must overcome several technical barriers. One possible cell-independent alternative direct administration small proteins myocardium. Methods and Results— Here we show that secreted signaling protein...
The BAR domain protein superfamily is involved in membrane invagination and endocytosis, but its role organizing proteins has not been explored. In particular, the scaffolding BIN1 functions to initiate T-tubule genesis skeletal muscle cells. Constitutive knockdown of mice perinatal lethal, which associated with an induced dilated hypertrophic cardiomyopathy. However, functional cardiomyocytes known. An important function cardiac T-tubules allow L-type calcium channels (Cav1.2) be close...
During each heartbeat, intercellular electrical coupling via connexin43 (Cx43) gap junctions enables synchronous cardiac contraction. In failing hearts, impaired Cx43 trafficking reduces junction coupling, resulting in arrhythmias. Here we report that internal translation within (GJA1) mRNA occurs, truncated isoforms autoregulate trafficking. We find at least four occur the human heart, with a 20 kDa isoform predominating. In-frame AUG codons GJA1 are initiation sites and their ablation...
The intracellular trafficking of connexin 43 (Cx43) hemichannels presents opportunities to regulate cardiomyocyte gap junction coupling. Although it is known that Cx43 are transported along microtubules the plasma membrane, role actin in forward unknown.We explored whether cytoskeleton involved trafficking.High-resolution imaging reveals vesicles colocalize with nonsarcomeric adult cardiomyocytes. Live-cell fluorescence as stationary or traveling slowly (average speed 0.09 μm/s) when...
Rapid electrical conduction in the His-Purkinje system tightly controls spatiotemporal activation of ventricles. Although recent work has shed much light on regulation early specification and morphogenesis system, less is known about how transcriptional establishes impulse properties constituent cells. Here we show that Iroquois homeobox gene 3 (Irx3) critical for efficient this specialized tissue by antithetically regulating two gap junction-forming connexins (Cxs). Loss Irx3 resulted...
Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized β1(SCN1B) -mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within (<30 nm) perinexal adjacent to gap junctions (GJs), facilitating coupling. Super-resolution imaging indicated preferential β1 localization at the perinexus, where it co-locates with...
BACKGROUND: Viral cardiac infection represents a significant clinical challenge encompassing several etiological agents, disease stages, complex presentation, and resulting lack of mechanistic understanding. Myocarditis is major cause sudden death in young adults, where current knowledge the field dominated by later phases pathological immune responses. However, little known regarding how can acutely induce an arrhythmogenic substrate before Adenovirus leading myocarditis, but due to species...
The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and potential treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte been documented, but the mechanism is unknown. Full-length connexin 43 (Cx43, encoded by GJA1) truncated, internally translated isoform GJA1-20k have implicated in between highly oxidative cells, not explored orthopaedic tissues. Here, our goal...
Altered phosphorylation and trafficking of connexin 43 (Cx43) during acute ischemia contributes to arrhythmogenic gap junction remodeling, yet the critical sequence accessory proteins necessary for Cx43 internalization remain unresolved. 14-3-3 can regulate protein trafficking, a mode-1 binding motif is activated upon Ser373 C-terminus. We hypothesized that Cx43(Ser373) important pathological remodeling. Immunofluorescence in human heart reveals enrichment at intercalated discs, suggesting...
Epithelial–mesenchymal transition (EMT) is activated during development, wound healing, and pathologies including fibrosis cancer metastasis. Hallmarks of EMT are remodeling intercellular junctions adhesion proteins, gap junctions. The GJA1 mRNA transcript encoding the junction protein connexin43 (Cx43) has been demonstrated to undergo internal translation initiation, yielding truncated isoforms that modulate PI3K/Akt/mTOR pathway central regulation EMT, leading us hypothesize altered...
Ovarian cancer is the deadliest gynecological in women, with a survival rate of less than 30% when has spread throughout peritoneal cavity. Aggregation cells increases their viability and metastatic potential; however, there are limited studies that correlate these functional changes to specific phenotypic alterations. In this study, we investigated mitochondrial morphology dynamics during malignant transition using our MOSE cell model for progressive serous ovarian cancer. Mitochondrial was...
Our laboratory previously demonstrated that perfusate sodium and potassium concentrations can modulate cardiac conduction velocity (CV) consistent with theoretical predictions of ephaptic coupling (EpC). EpC depends on the ionic currents intercellular separation in channel rich intercalated disk microdomains like perinexus. We suggested perinexal width (WP) correlates changes extracellular calcium ([Ca(2+)]o). Here, we test hypothesis increasing [Ca(2+)]o reduces WP increases CV....
Cardiac conduction is understood to occur through gap junctions. Recent evidence supports ephaptic coupling as another mechanism of electrical communication in the heart. Conduction via junctions predicts a direct relationship between velocity (CV) and bulk extracellular resistance. By contrast, theory premised on existence biphasic CV volume specialized clefts within intercalated discs such perinexus. Our objective was determine ventricular structural changes micro- nanoscale spaces.
Background: Tumor Necrosis Factor α (TNFα) upregulation during acute inflammatory response has been associated with numerous cardiac effects including modulating Connexin43 and vascular permeability. This may in turn alter gap junctional (GJ) coupling extracellular volume (ephaptic coupling) respectively. We hypothesized that exposure to pathophysiological TNFα levels can modulate conduction velocity (CV) the heart by altering electrical coupling: GJ ephaptic. Methods Results: Hearts were...
Adenoviruses are responsible for a spectrum of pathogenesis including viral myocarditis. The gap junction protein connexin43 (Cx43, gene name GJA1) facilitates rapid propagation action potentials necessary each heartbeat. Gap junctions also propagate innate and adaptive antiviral immune responses, but how viruses may target these structures is not understood. Given this immunological role Cx43, we hypothesized that would be targeted during adenovirus type 5 (Ad5) infection. We find reduced...
Abstract Background The phenomenon of intercellular mitochondrial transfer from mesenchymal stromal cells (MSCs) has shown promise for improving tissue healing after injury and potential treating degenerative diseases like osteoarthritis (OA). Recently MSC to chondrocyte been documented, but the mechanism is unknown. Full-length connexin43 (Cx43, encoded by GJA1 ) truncated internally translated isoform GJA1-20k have implicated in between highly oxidative cells, not explored orthopaedic...