A5032209720- Cancer, Hypoxia, and Metabolism
- Metabolism, Diabetes, and Cancer
- Muscle metabolism and nutrition
- Advanced MRI Techniques and Applications
- Cardiovascular Function and Risk Factors
- Cardiac Ischemia and Reperfusion
- Cancer-related Molecular Pathways
- Adipose Tissue and Metabolism
- Diet and metabolism studies
- Diabetes and associated disorders
- Endometriosis Research and Treatment
- Estrogen and related hormone effects
- Metabolism and Genetic Disorders
- Metabolomics and Mass Spectrometry Studies
- Nitric Oxide and Endothelin Effects
- RNA modifications and cancer
- Cardiovascular and exercise physiology
- Pancreatic function and diabetes
- Mitochondrial Function and Pathology
- Cardiac electrophysiology and arrhythmias
- Reproductive System and Pregnancy
- Cardiac Imaging and Diagnostics
- Adipokines, Inflammation, and Metabolic Diseases
- Regulation of Appetite and Obesity
- Receptor Mechanisms and Signaling
British Heart Foundation
2013-2024
University of Oxford
2015-2024
Centre for Human Genetics
2010-2022
Ludwig-Maximilians-Universität München
2017
Universität Hamburg
2017
University Medical Center Hamburg-Eppendorf
2017
National Heart Lung and Blood Institute
2013
National Institutes of Health
2013
University of Warwick
1999-2009
Progestin withdrawal is a crucial event for the onset of labor in many mammalian species. However, humans mechanism functional progestin unclear, because concentrations do not drop maternal plasma preceding labor. We report presence two novel membrane receptors (mPRs), mPRalpha and mPRbeta, human myometrium that are differentially modulated during by steroids vitro. The mPRs coupled to inhibitory G proteins, resulting decline cAMP levels increased phosphorylation myosin light chain, both...
Although starvation-induced biochemical and metabolic changes are perceived by the hypothalamus, adrenal gland plays a key role in integration of activity energy balance, implicating feeding as major synchronizer rhythms hypothalamic-pituitary-adrenal (HPA) axis. Given that orexins involved regulating food intake activating HPA axis, we hypothesized deprivation, an acute challenge to systems regulate should elicit orexin receptor signaling at hypothalamic levels. Food deprivation induced...
Creatine is thought to be involved in the spatial and temporal buffering of ATP energetic organs such as heart skeletal muscle. depletion affects force generation during maximal stimulation, while reduced levels myocardial creatine are a hallmark failing heart, leading widely held view that important at high workloads under conditions pathological stress.We therefore hypothesised consequences creatine-deficiency mice would impaired running capacity, exacerbation failure following...
Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia heart failure. However, testing this hypothesis has not been possible since oral supplementation ineffectual at myocardial levels. We therefore used mice overexpressing transporter in the (CrT-OE) test first time whether elevated beneficial clinically relevant disease models of failure ischaemia/reperfusion (I/R)...
Nitric oxide (NO) is a key signalling molecule released by vascular endothelial cells that essential for health. Low NO bioactivity associated with cardiovascular diseases, such as hypertension, atherosclerosis, and heart failure donors are mainstay of drug treatment. However, many the development tolerance adverse effects, so new formulations controlled targeted release would be advantageous. Herein, we describe design characterisation novel delivery system via reaction acidified sodium...
Mitochondrial creatine kinase (MtCK) couples ATP production via oxidative phosphorylation to phosphocreatine in the cytosol, which acts as a mobile energy store available for regeneration of at times high demand. We hypothesized that elevating MtCK would be beneficial ischaemia-reperfusion (I/R) injury.Mice were created over-expressing sarcomeric gene with αMHC promoter Rosa26 locus (MtCK-OE) and compared wild-type (WT) littermates. activity was 27% higher than WT, no change other CK...
Creatine buffers cellular adenosine triphosphate (ATP) via the creatine kinase reaction. levels are reduced in heart failure, but their contribution to pathophysiology is unclear. Arginine:glycine amidinotransferase (AGAT) kidney catalyses both first step biosynthesis as well homoarginine (HA) synthesis. AGAT-/- mice fed a creatine-free diet have whole body creatine-deficiency. We hypothesized that would develop cardiac dysfunction and rescue by dietary imply causality.Withdrawal of provided...
Abstract Mitochondrial creatine kinase (Mt-CK) is a major determinant of cardiac energetic status and down-regulated in chronic heart failure, which may contribute to disease progression. We hypothesised that cardiomyocyte-specific overexpression Mt-CK would mitigate against these changes thereby preserve function. Male overexpressing mice (OE) WT littermates were subjected transverse aortic constriction (TAC) or sham surgery assessed by echocardiography at 0, 3 6 weeks alongside final LV...
We report the full genomic organization of human gene for corticotropin-releasing factor (CRF) receptor type 1 (CRFR1), with complete mapping exons 1-14. The 5' flanking region (2.4 kb) encoding CRFR1 was isolated, sequenced, and characterized. Two major transcriptional start sites were determined at -265 -238, relative to ATG site (+1). Transient expression constructs containing sequentially deleted 5'-flanking sequences fused luciferase, revealed minimal promoter sequence 370 bp in size,...
The creatine kinase (CK) phosphagen system is fundamental to cellular energy homeostasis. Cardiomyocytes express three CK isoforms, namely the mitochondrial sarcomeric CKMT2 and cytoplasmic CKM CKB. We hypothesized that augmenting in vitro would preserve cell viability function sought determine efficacy of various isoforms. open reading frame each isoform was cloned into pcDNA3.1, followed by transfection stable selection human embryonic kidney cells (HEK293). CKMT2- CKM- CKB-HEK293 had...
Tumour regression observed in many conditional mouse models following oncogene inactivation provides the impetus to develop, and a platform preclinically evaluate, novel therapeutics inactivate specific oncogenes. Inactivating single oncogenes, such as c-Myc, can reverse even advanced tumours. Intriguingly, transient c-Myc proved sufficient for sustained osteosarcoma regression; resulting osteocyte differentiation potentially explaining loss of c-Myc's oncogenic properties. But would this...
c-Myc (Myc) is a mediator of glucotoxicity but could also independently compromise β-cell survival and function. We have shown that after Myc activation in adult β-cells vivo, apoptosis preceded by hyperglycemia, suggesting might contribute to Myc-induced apoptosis. To address this question conditional was activated pIns-c-MycERTAM mice vivo the presence or absence various glucose-lowering treatments, including exogenous insulin prior transplantation with wild-type islets. Changes blood...
The creatine kinase (CK) energy transport and buffering system supports cardiac function at times of high demand is impaired in the failing heart. Mice deficient muscle- mitochondrial-CK (M/Mt-CK−/−) have previously been described, but exhibit an unexpectedly mild phenotype compensated left ventricular (LV) hypertrophy. We hypothesised that heart failure would develop with age performed echocardiography LV haemodynamics 1 year. Since all previous studies utilised mice a mixed genetic...
Inhibition of malonyl-coenzyme A decarboxylase (MCD) shifts metabolism from fatty acid towards glucose oxidation, which has therapeutic potential for obesity and myocardial ischemic injury. However, ~40% patients with MCD deficiency are diagnosed cardiomyopathy during infancy.To clarify the link between cardiac dysfunction in early life to determine contributing systemic metabolic perturbations.MCD knockout mice ((-/-)) exhibited non-Mendelian genotype ratios (31% fewer MCD(-/-)) deaths...
Mice over-expressing the creatine transporter have elevated myocardial levels [Cr] and are protected against ischaemia/reperfusion injury via improved energy reserve. However, mice with very high develop cardiac hypertrophy dysfunction. To investigate these contrasting effects, we applied a non-biased hypothesis-generating approach to quantify global protein metabolite changes in LV of stratified for levels: wildtype, moderately elevated, (65–85; 100–135; 160–250 nmol/mg protein,...
Abstract Hypoxia-inducible factor 1α is a key regulator of the hypoxia response in normal and cancer tissues. It well recognized to regulate glycolysis target for therapy. However, how tumor cells adapt grow absence HIF1α poorly understood an important concept understand developing targeted therapies flexibility metabolic via alternative pathways. We analyzed pathways that allow survive hypoxic stress HIF1α, using HCT116 colon cell line with deleted versus control. Spheroids were used...
This study was designed to investigate the association of 894G>T polymorphism in eNOS gene with risk acute myocardial infarction (AMI), extent coronary artery disease (CAD) on angiography, and in-hospital mortality after AMI. We studied 1602 consecutive patients who were enrolled GEMIG study. The control group comprised by 727 individuals, randomly selected from general adult population. prevalence Asp298 variant not found be significantly independently associated AMI (RR = 1.08, 95%CI...
Background Multiple studies suggest creatine mediates anti-oxidant activity in addition to its established role cellular energy metabolism. The functional significance for the heart has yet be established, but antioxidant could contribute cardioprotective effect of ischaemia/reperfusion injury. Objectives To determine whether intracellular levels influence responses acute reactive oxygen species (ROS) exposure intact beating heart. We hypothesised that mice with elevated due over-expression...
Aim: Guanidinoacetate N-methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency metabolically well tolerated as GAMT-/- mice exhibit normal exercise capacity and response to ischaemic heart failure. However, we hypothesised long-term consequences of and/or accumulation precursor guanidinoacetate (GA). Methods: Cardiac function metabolic profile were studied >1 year. Results: In vivo LV catheterisation revealed lower rate developed...