A5035744973- Osteoarthritis Treatment and Mechanisms
- Cancer-related molecular mechanisms research
- Rheumatoid Arthritis Research and Therapies
- Systemic Lupus Erythematosus Research
- Cytokine Signaling Pathways and Interactions
- Immunodeficiency and Autoimmune Disorders
- Monoclonal and Polyclonal Antibodies Research
- T-cell and B-cell Immunology
- interferon and immune responses
- Epigenetics and DNA Methylation
- Lymphoma Diagnosis and Treatment
- Cancer-related gene regulation
- Immune Cell Function and Interaction
- MicroRNA in disease regulation
- Salivary Gland Disorders and Functions
- Chronic Lymphocytic Leukemia Research
- Mycobacterium research and diagnosis
- Circular RNAs in diseases
- Psoriasis: Treatment and Pathogenesis
- Protease and Inhibitor Mechanisms
- Molecular Biology Techniques and Applications
- Cell Adhesion Molecules Research
- RNA modifications and cancer
- IL-33, ST2, and ILC Pathways
- Genetics and Neurodevelopmental Disorders
UCB Pharma (United Kingdom)
2019-2025
UCB Pharma (Belgium)
2023-2024
Newcastle University
2015-2023
Amsterdam University Medical Centers
2023
University Medical Center Utrecht
2023
Centre for Life
2019
NIHR Newcastle Biomedical Research Centre
2015-2019
Newcastle upon Tyne Hospitals NHS Foundation Trust
2015-2019
National Institute for Health Research
2015-2019
Versus Arthritis
2018
Human IFNAR2 deficiency causes fatal susceptibility to live viral vaccines.
Abstract Autoimmunity can occur when a checkpoint of self-tolerance fails. The study familial autoimmune diseases reveal pathophysiological mechanisms involved in more common diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations the SOCS1 gene ten patients from five unrelated families with early onset manifestations. intracellular protein is known to downregulate cytokine signaling inhibiting JAK-STAT pathway....
Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed develop robust method stratification, exploiting heterogeneity in patient-reported symptoms, and relate these differences pathobiology therapeutic response.
STAT2 R148W impairs an essential regulatory function of STAT2, revealing the damage wreaked by excessive IFNα/β activity.
Abstract Metabolic programming is important for B cell fate, but the bioenergetic requirement regulatory (B reg ) differentiation and function unknown. Here we show that differentiation, unlike non-B cells, relies on mitochondrial electron transport homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed TXN , encoding metabolic redox protein thioredoxin (Trx), highly expressed by Trx inhibitor TXNIP which was downregulated. Pharmacological...
Long non-coding RNAs (lncRNAs) are expressed in a highly tissue-specific manner and function various aspects of cell biology, often as key regulators gene expression. In this study, we established role for lncRNAs chondrocyte differentiation. Using RNA sequencing identified human articular repertoire from normal hip cartilage donated by neck femur fracture patients. Of particular interest upstream the master transcription factor SOX9 locus. is an HMG-box that plays essential development...
Irreversible breakdown of cartilage extracellular matrix (ECM) by the collagenase metalloproteinase 13 (MMP13) represents a key event in osteoarthritis (OA) progression. Although inflammation is most commonly associated with inflammatory joint diseases, it also occurs OA and thus relevant to prevalent tissue destruction. Here, generates cFOS AP-1 early response that indirectly affects MMP13 gene expression. To ascertain more direct effect on prolonged production we examined potential...
Objective To identify the functional single‐nucleotide polymorphisms (SNPs) and mechanisms conferring increased risk of hand osteoarthritis (OA) at ALDH1A2 locus, which is a retinoic acid regulatory gene. Methods Tissue samples from 247 patients with knee, hip, or OA who had undergone joint surgery were included. RNA‐sequencing analysis was used to investigate differential expression other signaling pathway genes in cartilage. Expression tissues obtained multiple sites quantified using...
Many patients with rheumatoid arthritis (RA) achieve disease remission modern treatment strategies. However, having achieved this state, there are no tests that predict when withdrawal of therapy will result in drug-free rather than flare. We aimed to identify predictors RA.The Biomarkers Remission Rheumatoid Arthritis (BioRRA) Study was a unique, prospective, interventional cohort study complete and abrupt cessation conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs)....
Objective To identify methylation quantitative trait loci ( mQTL s) correlating with osteoarthritis OA ) risk alleles and to undertake mechanistic characterization as a means of target gene prioritization. Methods We used genome‐wide genotyping cartilage DNA array data in discovery screen novel loci. This was followed by methylation, expression analysis, studies additional samples, accompanied silico analyses. Results identified 4 s. The most significant contained 9 CpG sites where...
ObjectiveLong intergenic non-coding RNAs (lincRNAs) are emerging as key regulators in gene expression; however, little is known about the lincRNA expression changes that occur osteoarthritis (OA). Here we aimed to define a transcriptome of lncRNAs OA cartilage, specifically comparing knee and hip cartilage.MethodRNA-seq was performed on nucleic acid extracted from cartilage patients undergoing joint replacement surgery because either (n = 10) or neck femur fracture (NOF; n 6). After...
Objective Rheumatoid arthritis ( RA ) is a genetically complex disease of immune dysregulation. This study sought to gain further insight into the genetic risk mechanisms by conducting an expression quantitative trait locus eQTL analysis confirmed loci in CD 4+ T cells and B from carefully phenotyped patients with early who were naive therapeutic immunomodulation. Methods RNA DNA isolated purified and/or obtained peripheral blood 344 arthritis. Genotyping global gene measurements carried out...
BackgroundDefining regulatory mechanisms through which noncoding risk variants influence the cell-mediated pathogenesis of immune-mediated disease (IMD) has emerged as a priority in post–genome-wide association study era.ObjectivesWith focus on rheumatoid arthritis, we sought new insight into genetic adaptive immune dysregulation to help prioritize molecular pathways for targeting this and related pathologies.MethodsWhole-genome methylation transcriptional data from isolated CD4+ T cells B...
Abstract Epilepsy is a chronic and heterogenous disease characterized by recurrent unprovoked seizures, that are commonly resistant to antiseizure medications. This study applies transcriptome network-based approach across epilepsies aiming improve understanding of molecular pathobiology, recognize affected biological mechanisms apply causal reasoning identify therapeutic hypotheses. included the most common drug-resistant (DREs), such as temporal lobe epilepsy with hippocampal sclerosis...
Objective: Dendritic cells (DCs) are key orchestrators of immune function. To date, rheumatoid arthritis (RA) researchers have predominantly focused on a potential pathogenic role for CD1c+ DCs. In contrast, CD141+ DCs and plasmacytoid (pDCs) not been systematically examined, at least in early RA. established RA the pDCs is ambiguous and, since disease duration treatment both impact pathophysiology, we examined pDCs, conventional (cDCs), early, drug-naïve (eRA) patients. Methods: We analysed...
Abstract Regulation of transcription occurs in a cell type specific manner orchestrated by epigenetic mechanisms including DNA methylation. Methylation changes may also play key role lineage specification during stem differentiation. To further our understanding regulation chondrocytes we characterised the methylation chondrogenesis mesenchymal cells (MSCs) Infinium 450 K array. Significant hypomethylation was identified chondrogenic differentiation at many cartilage gene loci. Integration...
Introduction Gingival fibroblast-mediated extracellular matrix remodelling is implicated in the pathogenesis of periodontitis, yet stimuli that regulate this response are not fully understood. The immunoregulatory adipokine leptin detectable gingiva, human gingival fibroblasts express functional receptor mRNA and known to responses cardiac fibroblasts. We therefore hypothesised would enhance metalloproteinase secretion Methods Results used vitro cell culture investigate signalling effect on...
miR-140 is selectively expressed in cartilage. Deletion of the entire Mir140 locus mice results growth retardation and early-onset osteoarthritis-like pathology; however, relative contribution miR-140-5p or miR-140-3p to phenotype remains be determined. An unbiased small RNA sequencing approach identified as significantly more abundant (>10-fold) than human Analysis these data multiple isomiRs differing from miRBase annotation at both 5′ 3′ end, with >99% having one two seed sequences...
Osteoarthritis (OA) is a painful, debilitating disease characterised by loss of articular cartilage with concurrent changes in other tissues the synovial joint. Genetic association studies have shown that number common variants increase risk developing OA. Investigating their activity can uncover novel causal pathways and potentially highlight new treatment targets. One reported OA signals marked single nucleotide polymorphism (SNP) rs11842874 at chromosome 13q34. positioned within small...
Objective: We have previously shown that increased circulating interleukin-6 (IL-6) results in enhanced CD4+ T-cell signalling via signal transduction and activator of transcription-3 (STAT3) early RA. tested the hypothesis transcriptional "imprinting" T-cells by this mechanism skews downstream effector responses, reinforcing immune dysregulation at a critical, but targetable, disease phase. Methods: modelled naïve T cell exposure to pathophysiological concentrations IL-6 vitro, assessing...