A5067253322- Ion channel regulation and function
- Cancer, Hypoxia, and Metabolism
- Cardiac electrophysiology and arrhythmias
- RNA Research and Splicing
- Receptor Mechanisms and Signaling
- Esophageal and GI Pathology
- Epigenetics and DNA Methylation
- Ion Channels and Receptors
- RNA modifications and cancer
- Neuroscience and Neuropharmacology Research
- Nitric Oxide and Endothelin Effects
- Eicosanoids and Hypertension Pharmacology
- Genetics, Aging, and Longevity in Model Organisms
- Gene Regulatory Network Analysis
- Genomics and Chromatin Dynamics
- Gastroesophageal reflux and treatments
- Cardiac Ischemia and Reperfusion
- Immune Response and Inflammation
- Neurobiology and Insect Physiology Research
- Mitochondrial Function and Pathology
- bioluminescence and chemiluminescence research
- Abdominal Surgery and Complications
- Cancer-related molecular mechanisms research
- Inflammatory Bowel Disease
- interferon and immune responses
Aston University
2014-2023
University College Dublin
2010-2018
University of Leeds
2001-2010
University of Virginia
2008
University of Missouri
2008
University of California, Davis
2008
Institute of Materials, Minerals and Mining
2006
Aichi Gakuin University
2006
Leeds General Infirmary
2006
University of Campania "Luigi Vanvitelli"
2006
The hypoxia-inducible factor (HIF) is a key regulator of the transcriptional response to hypoxia. While mechanism underpinning HIF activation well understood, little known about its resolution. Both protein and mRNA levels HIF-1α (but not HIF-2α) were decreased in intestinal epithelial cells exposed prolonged Coincident with this, microRNA (miRNA) array analysis revealed multiple miRNAs. Among these was miRNA-155 (miR-155), which predicted target mRNA. We confirmed hypoxic upregulation...
Occlusive vascular disease is a widespread abnormality leading to lethal or debilitating outcomes such as myocardial infarction and stroke. It part of atherosclerosis evoked by clinical procedures including angioplasty grafting saphenous vein in bypass surgery. A causative factor the switch smooth muscle cells an invasive proliferative mode, neointimal hyperplasia. Here we reveal importance this process TRPC1, homolog Drosophila transient receptor potential. Using 2 different vivo models...
Significance Oxygen-sensing hydroxylases are a family of enzymes that control the cellular adaptive response to hypoxia. Hydroxylase inhibitors reduce inflammation in vivo; however, anti-inflammatory mechanism action remains unclear. IL-1β is cytokine potently promotes through activation transcription factor NF-κB. Here, we demonstrate hydroxylase inhibition leads suppression IL-1β–induced NF-κB activity and provide insight into underlying involved. This work develops our understanding how...
Activation of the hypoxia-inducible factor (HIF) pathway is a critical step in transcriptional response to hypoxia. While many key proteins involved have been characterised, dynamics their interactions generating this remain unclear. We generated comprehensive mathematical model HIF-1α based on core validated components and dynamic experimental data, confirm previously described connections within predicted network topology. Our confirms previous work demonstrating that steps leading optimal...
In a screen of potential lipid regulators transient receptor (TRP) channels, we identified sphingosine-1-phosphate (S1P) as an activator TRPC5. We explored the relevance to vascular biology because S1P is key cardiovascular signaling molecule. TRPC5 expressed in smooth muscle cells human vein along with TRPC1, which forms complex Importantly, also activates TRPC5-TRPC1 heteromultimeric channel. Because TRPC channels are linked neuronal growth cone extension, considered related concept for...
We previously demonstrated that upregulation of intermediate-conductance Ca(2+)-activated K(+) channels (K(Ca)3.1) is necessary for mitogen-induced phenotypic modulation in isolated porcine coronary smooth muscle cells (SMCs). The objective the present study was to determine role K(Ca)3.1 regulation SMC vivo using a swine model postangioplasty restenosis.Balloon angioplasty performed on arteries either noncoated or balloons coated with specific blocker TRAM-34. Expression K(Ca)3.1, c-jun,...
Abstract Cellular exposure to hypoxia results in altered gene expression a range of physiologic and pathophysiologic states. Discrete cohorts genes can be either up- or down-regulated response hypoxia. While the Hypoxia-Inducible Factor (HIF) is primary driver hypoxia-induced adaptive expression, less known about signalling mechanisms regulating hypoxia-dependent repression. Using RNA-seq, we demonstrate that equivalent numbers are induced repressed human embryonic kidney (HEK293) cells. We...
Oxygen is a crucial molecule for cellular function. When oxygen demand exceeds supply, the sensing pathway centred on hypoxia inducible factor (HIF) switched and promotes adaptation to by up-regulating genes involved in angiogenesis, erythropoiesis glycolysis. The regulation of HIF tightly modulated through intricate regulatory mechanisms. Notably, its protein stability controlled prolyl hydroxylase domain (PHD) enzymes transcriptional activity asparaginyl FIH (factor inhibiting HIF-1).To...
Abstract The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation deprivation. However, degree duration HIF-1α expression in must be carefully balanced within cells order avoid unwanted side effects associated with excessive activity. mRNA suppressed prolonged hypoxia, suggesting that control HIF1A gene transcription tightly regulated by negative feedback mechanisms. Little known about resolution protein...
Under conditions of hypoxia, most eukaryotic cells undergo a shift in metabolic strategy, which involves increased flux through the glycolytic pathway. Although this is critical for bioenergetic homeostasis, underlying mechanisms have remained incompletely understood. Here, we report that induction hypoxia-induced glycolysis retained when gene transcription or protein synthesis are inhibited suggesting involvement additional post-translational mechanisms. Post-translational modification by...
AimThe aim of the study was to determine potential for KV1 potassium channel blockers as inhibitors human neoinitimal hyperplasia.
1 In this study we investigated the expression and function of KVα1 subfamily voltage-gated K+ channels in terminal arterioles from rabbit cerebral circulation. 2 current was measured smooth muscle cells within intact freshly isolated arteriolar fragments. Current activated on depolarisation positive about –45 mV a large fraction blocked by 3,4-diaminopyridine (3,4-DAP) or 4-aminopyridine (4-AP), inhibitors KV channels. Expression cRNA encoding KV1.6 Xenopus oocytes also generated...
The primary objectives of this study were to reveal cell-specific expression patterns and functions voltage-gated K(+) channel (K(V)alpha1) subunits in precapillary arterioles the murine cerebral circulation. K(V)alpha1 detected using peptide-specific antibodies immunofluorescence Western blotting assays. K(V)1.2 was localized almost exclusively endothelial cells, whereas K(V)1.5 discretely nerves nerve terminals that innervate arterioles. also specifically arteriolar human pial membrane....
This study tested the hypothesis that store-operated channels (SOCs) exist as a discrete population of Ca2+ activated by depletion intracellular Ca(2+) stores in cerebral arteriolar smooth muscle cells and explored their direct contractile function. Using indicator fura-PE3 it was observed sarcoplasmic reticulum (SR) inhibition SR Ca2+-ATPase (SERCA) led to sustained elevation [Ca2+]i depended on extracellular slightly enhanced Mn2+ entry. Enhanced background influx did not explain raised...
This study focused on the hypothesis that KCNA genes (which encode K(V)alpha1 voltage-gated K(+) channels) have enhanced functional expression in smooth muscle cells of a primary determinant peripheral resistance - small mesenteric artery. Real-time PCR methodology was developed to measure cell type-specific situ gene expression. Profiles were determined for arterial myocyte RNA species encoding subunits as well K(V)beta1, K(V)alpha2.1, K(V)gamma9.3, BK(Ca)alpha1 and BK(Ca)beta1. The seven...
We show theoretically and experimentally a mechanism behind the emergence of wide or bimodal protein distributions in biochemical networks with nonlinear input–output characteristics (the dose–response curve) variability abundance. Large cell-to-cell variation can be beneficial to facilitate two distinct groups response levels as opposed graded response. Under circumstances that we quantify mathematically, responses coexist within cellular population, leading distribution. Using flow...
Fibrosis is a complication of chronic inflammatory disorders such as bowel disease, condition which has limited therapeutic options and often requires surgical intervention. Pharmacologic inhibition oxygen-sensing prolyl hydroxylases, confer oxygen sensitivity upon the hypoxia-inducible factor pathway, recently been shown to have potential in colitis, although mechanisms involved remain unclear. Here, we investigated impact hydroxylase on inflammation-driven fibrosis murine colitis model....
Cyclooxygenase 2 (COX2), a key regulatory enzyme of the prostaglandin/eicosanoid pathway, is an important target for anti-inflammatory therapy. It highly induced by pro-inflammatory cytokines in Nuclear factor kappa B (NFκB)-dependent manner. However, mechanisms determining amplitude and dynamics this event are poorly understood. Furthermore, there significant difference between human mouse COX2 expression response to inflammatory stimulus tumor necrosis alpha (TNFα). Here, we report...
K(V)1.5, a voltage-gated potassium channel, has functional importance in regulating blood vessel tone and cardiac action potentials is target for numerous therapeutic drug development programs. Despite the of there little knowledge mechanisms controlling expression its underlying gene, Kcna5. We identified 5' flanking region murine Kcna5 gene that drives luciferase reporter primary smooth muscle cells cell line. The promoter contained CACCC nucleotide motifs, which we have shown to bind Sp1...
A human aorta cDNA library was screened at low stringency with a rat pancreatic Kir6.1 probe and homologue of (hKir6.1) isolated sequenced. Metabolic poisoning Xenopus laevis oocytes sodium azide application the K + channel opener drug diazoxide induced currents in co‐injected cRNA for hKir6.1 hamster sulphonylurea receptor (SUR1), but not injected water or SUR1 alone. due to hKir6.1+SUR1 mouse Kir6.2+SUR1 were strongly inhibited by 1 μ M glibenclamide. ‐current carried putative...