A5076716094- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- Folate and B Vitamins Research
- Cardiomyopathy and Myosin Studies
- Genetics and Neurodevelopmental Disorders
- Heme Oxygenase-1 and Carbon Monoxide
- Esophageal and GI Pathology
- Cardiovascular Health and Disease Prevention
- Epigenetics and DNA Methylation
- Muscle Physiology and Disorders
- Cerebrovascular and genetic disorders
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Protein Tyrosine Phosphatases
- Cell Adhesion Molecules Research
- Angiogenesis and VEGF in Cancer
- Paraoxonase enzyme and polymorphisms
- Hernia repair and management
- Peroxisome Proliferator-Activated Receptors
- Antiplatelet Therapy and Cardiovascular Diseases
- RNA Research and Splicing
- Cytokine Signaling Pathways and Interactions
- Thermal Regulation in Medicine
- Neuroinflammation and Neurodegeneration Mechanisms
- Nitric Oxide and Endothelin Effects
- Eicosanoids and Hypertension Pharmacology
University College London
2016-2024
National Hospital for Neurology and Neurosurgery
2018-2024
UK Dementia Research Institute
2018-2020
Huntington's Disease Association
2016
King's College London
2004-2014
Hammersmith Hospital
2009-2012
Imperial College London
2008-2012
St George's Hospital
2001-2002
St George's, University of London
2001-2002
King's College Hospital
2001-2002
Background and Purpose A common polymorphism ( T / t ) in the gene encoding methylenetetrahydrofolate reductase (MTHFR) enzyme has been associated with elevated serum homocysteine, itself a risk factor for stroke. Some studies have reported an association ischemic heart disease, but no published examined its relationship Methods We determined TT genotype frequency allele 345 patients cerebrovascular disease (CVD) 161 control subjects. In subgroup we also homocysteine folate concentrations....
Background and Purpose —The role of endothelial nitric oxide synthase (eNOS) in normal physiology suggests that it could be a potential candidate gene for stroke. Reduced eNOS activity mediate an increased stroke risk through hypertension or independent abnormal vasomotor responses, promoting atherogenesis, platelet adhesion aggregation. Recently, common polymorphism exon 7 the (894G→T) has been reported to strong factor coronary artery disease. We determined whether was also transient...
Abstract Huntington’s disease is caused by the expansion of a CAG repeat within exon 1 HTT gene, which unstable, leading to further expansion, extent brain region and peripheral tissue specific. The identification DNA repair genes as genetic modifiers disease, that were known abrogate somatic instability in mouse models, demonstrated central pathogenesis, threshold for pathogenesis specific cells might not be known. We have previously shown gene incompletely spliced generating small...
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily ligand-activated transcriptional regulators. PPARdelta has an established role in metabolism, wound healing, and angiogenesis. However, little is known about its function endothelial homeostasis. We investigated co-activator, PPARgamma co-activator 1alpha (PGC1alpha), vasculoprotection against oxidant-induced injury via induction haem oxygenase-1.En face confocal microscopy murine aortas...
Neurodegenerative diseases, characterised by the progressive and selective neuronal death in central nervous system, are frequently accompanied an activated immune system. In Huntington's disease (HD), clinical animal studies show evidence of activity, along with hyper-reactive monocyte/macrophage responses, while application immunosuppressive regimens have imparted beneficial effects to HD mice. These findings suggest a contributory role system pathology, immune-based interventions offering...
Abstract Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat within the huntingtin ( HTT ) gene. The Q140 and Hdh Q150 knock‐in HD mouse models were generated such that mice have inserted into Htt gene, whereas in Q140s, exon 1 was replaced with mutated version of human 1. By standardizing strain background, breeding to homozygosity employing sensitive behavioral tests, we demonstrate onset phenotypes occurs earlier than (HTT) aggregation...
Individuals of African Caribbean descent who live in the United Kingdom have an increased risk stroke. The reasons for this are not fully understood, but differences genetic predispositions or other novel stroke factors could play a role. US blacks been reported to common carotid artery wall thickness, intima-media thickness (IMT), measured by ultrasound. We IMT UK Caribbeans compared with whites and determined whether different distributions polymorphisms potential candidate vascular genes...
Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy a common feature, and multiple lines evidence support muscle-based pathophysiology in HD mouse models. Inhibition myostatin signaling increases mass, therapeutic approaches based on this are clinical development. We have used soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects myostatin/activin A inhibition R6/2 model HD. Weekly administration from 5 11 weeks age...
Vascular endothelial injury predisposes to dysfunction and atherogenesis. We have investigated the hypothesis that PKCϵ (protein kinase Cϵ) is an important upstream regulator of cytoprotective pathways in vascular ECs (endothelial cells). Depletion human reduced expression genes A1, A20 Bcl-2. Conversely, constitutively active expressed increased mRNA protein levels these genes, with up-regulation dependent upon ERK1/2 (extracellular-signal-regulated 1/2) activation. Furthermore, inhibition...
Abstract Huntington’s disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion that encodes polyglutamine tract in the huntingtin (HTT) protein. The mutant unstable and expands specific brain cells peripheral tissues throughout life. Genes involved DNA mismatch repair pathways, known to act on expansion, have been identified as genetic modifiers; therefore, it rate of somatic drives age onset progression. In context expanded repeat, HTT pre-mRNA can be...
The atrial natriuretic peptide (ANP) gene may underlie stroke susceptibility and sensitivity to cerebral ischemia in an animal model of stroke. authors investigate its role humans by genotyping a polymorphism (<i>G664A</i>) 436 patients with ischemic cerebrovascular disease 295 community control subjects. frequency this variant was similar both groups across the different subtypes. ANP <i>G664A</i> is therefore unlikely be important risk factor for population.
ABSTRACT Huntington’s disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion that encodes polyglutamine tract in the HTT protein. The mutant unstable and expands specific brain cells peripheral tissues throughout life. Genes involved DNA mismatch repair pathways, known to act on expansion, have been identified as genetics modifiers, therefore, it rate of somatic drives age onset progression. In context expanded repeat, pre-mRNA can be alternatively processed...
Summary Duodenal volvulus is an extremely rare condition, with few cases reported in the literature. We present case of 83‐year‐old man spontaneous duodenal diagnosed on CT imaging. Findings included third part duodenum, characteristic whirl pattern superior mesenteric vessels and medialisation gallbladder. He was treated nasogastric tube decompression follow‐up demonstrated complete resolution volvulus.
<h3>Background</h3> The zQ175 knock-in line was generated by replacing mouse endogenous Htt exon 1 with a mutant version of human HTT followed the expansion CAG repeat. This is now being used extensively throughout HD research community. <h3>Method</h3> We have performed molecular analysis to study changes in and appearance transcriptional dysregulation. immunoprecipitation western blotting visualise fragments found that level fragment decreased from two months age. <h3>Results</h3> Seprion...
<h3>Background</h3> The R6/2 mouse model of Huntington’s disease (HD) is one the most widely used models in HD research and contains human exon1 HTT with a CAG/polyglutamine (polyQ) repeat expansion. When created line had expansion approximately 150Q because gametic CAG instability, colonies throughout world now have wide range sizes. <h3>Methods</h3> We assessed behavioural molecular phenotypes an comparatively stable polyQ-repeat 90Q. These mice show slower progression end point at around...
<h3>Background</h3> The ability to monitor clinical trials in Huntington’s disease (HD) patients with pharmacodynamic read outs will be essential, and PET ligands that give altered signals HD patient brains are being considered for use monitoring huntingtin-lowering strategies. However, there many have never been assessed brains. As a first step the investigation as which of these might provide useful biomarkers HD, we determined whether transcript levels genes encoding dysregulated mouse...
<h3>Background</h3> We have previously shown that the <i>HTT</i> gene is incompletely spliced to generated a small exon 1 – intron polyadenylated mRNA translated produce an HTT protein. This occurs in all knock-in mouse models of HD, YAC128 mice, BACHD mice and patient tissues. Through bioinformatics, we predicted splicing factor SRSF6 binds degenerative motif includes both (CAG)n (CAGCAA)n sequences proposed ectopic recruitment related this aberrant event. <h3>Aims</h3> To compare effect...
<h3>Background</h3> We have previously shown that exon 1 of the huntingtin gene does not always splice to 2 resulting in production a small polyadenylated mRNA encodes highly pathogenic HTT protein. The level this read-through product is proportional CAG repeat length and present all knock-in mouse models HD (with ≥ 50), utilising cryptic polyadenylation sites located at 677 bp 1145 into intron 1. also readily detected YAC128 BACHD which both use site 7327 human However, presence – was easy...
Background: Heme oxygenase‐1 (HO‐1) and decay‐accelerating factor (DAF) are endothelial cytoprotective genes which limit vascular injury. Statins induce DAF, while rapamycin (Rap) upregulates HO‐1 expression. We asked whether statins Rap act synergistically to enhance vasculoprotection. Methods & Results: Treatment of EC with atorvastatin (AT) 0.5μM 1.25μM led a synergistic increase in DAF expression 24‐72h post‐treatment (>200%, p<0.05). AT + Rap‐induced was dependent upon gene...