A5078000284- Circadian rhythm and melatonin
- Spaceflight effects on biology
- Dietary Effects on Health
- Spine and Intervertebral Disc Pathology
- Ubiquitin and proteasome pathways
- High Altitude and Hypoxia
- Adipose Tissue and Metabolism
- Musculoskeletal pain and rehabilitation
- Genetics, Aging, and Longevity in Model Organisms
- Asthma and respiratory diseases
- Heat shock proteins research
- Olfactory and Sensory Function Studies
- Neurobiology and Insect Physiology Research
- Climate Change and Health Impacts
- ATP Synthase and ATPases Research
- Advanced Chemical Sensor Technologies
- Infrared Thermography in Medicine
- Peptidase Inhibition and Analysis
- Coenzyme Q10 studies and effects
- Pregnancy-related medical research
- Skin and Cellular Biology Research
- Antioxidants, Aging, Portulaca oleracea
- NF-κB Signaling Pathways
- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
Wellcome Centre for Cell-Matrix Research
2014-2024
University of Manchester
2014-2024
Manchester Academic Health Science Centre
2019-2024
Osteoarthritis (OA) is the most prevalent and debilitating joint disease, there are currently no effective disease-modifying treatments available. Multiple risk factors for OA, such as aging, result in progressive damage loss of articular cartilage. Autonomous circadian clocks have been identified mouse cartilage, environmental disruption rhythms mice predisposes animals to OA-like damage. However, contribution cartilage clock mechanisms maintenance tissue homeostasis still unclear. Here, we...
Abstract Optimum protein function and biochemical activity critically depends on water availability because solvent thermodynamics drive folding macromolecular interactions 1 . Reciprocally, macromolecules restrict the movement of ‘structured’ molecules within their hydration layers, reducing available ‘free’ bulk therefore total thermodynamic potential energy water, or potential. Here, concentrated solutions such as cytosol, we found that modest changes in temperature greatly affect...
Objectives The circadian clocks are internal timing mechanisms that drive ∼24-hour rhythms in a tissue-specific manner. Many aspects of the physiology intervertebral disc (IVD) show clear diurnal rhythms. However, it is unknown whether IVD tissue contains functional and if so, how their dysregulation implicated degeneration. Methods Clock gene dynamics ex vivo explants (from PER2:: luciferase (LUC) reporter mice) human cells (transduced with lentivirus containing Per2 ::luc reporters) were...
The circadian clock in mammals temporally coordinates physiological and behavioural processes to anticipate daily rhythmic changes their environment. Chronic disruption rhythms (e.g., through ageing or shift work) is thought contribute a multitude of diseases, including degeneration the musculoskeletal system. intervertebral disc (IVD) spine contains clocks which control ∼6% transcriptome manner, key genes involved extracellular matrix (ECM) homeostasis. However, it remains largely unknown...
The night and day cycle governs the circadian (24 hourly) rhythm of activity rest in animals humans. This is reflected daily changes global gene expression pattern metabolism, but also local physiology various tissues. A central clock brain co-ordinates rhythmic locomotion behaviour, as well synchronizing oscillators, such those found musculoskeletal system. It has become increasingly recognized that internal molecular clocks cells allow a tissue to anticipate their environment specific...
ObjectiveTo define how the catabolic cytokines (Interleukin 1 (IL-1) and tumor necrosis factor alpha (TNFα)) affect circadian clock mechanism expression of clock-controlled genes within cartilage, to identify downstream pathways linking molecular chondrocytes.MethodsEx vivo cartilage explants were isolated from Cry1-luc or PER2::LUC reporter mice. Clock gene dynamics monitored in real-time by bioluminescence photon counting. Gene changes studied qRT-PCR. Functional luc assays used study...
The circadian clock participates in maintaining homeostasis peripheral tissues, including intervertebral discs (IVDs). Abnormal mechanical loading is a known risk factor for disc degeneration (IDD). Based on the rhythmic daily pattern of rest and activity, we hypothesized that abnormal could dampen IVD clock, contributing to IDD. Here, investigated effects aimed inhibit compression-induced IDD by targeting core molecule brain muscle Arnt-like protein-1 (BMAL1). In this study, showed BMAL1 KO...
Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light feeding). The presence of tissue niche-dependent physiological time has been proposed, allowing tissues the ability phase adjustment based on local signals. However, to date, such stimuli have remained elusive. Here we show that daily patterns mechanical loading associated osmotic challenge within ranges reset clock amplitude cartilage...
Evolutionarily conserved circadian clocks generate 24-hour rhythms in physiology and behaviour that adapt organisms to their daily seasonal environments. In mammals, the suprachiasmatic nucleus (SCN) of hypothalamus is principal co-ordinator cell-autonomous distributed across all major tissues. The importance robust highlighted by experimental epidemiological associations between disruption human diseases. BMAL1 (a bHLH-PAS domain-containing transcription factor) master positive regulator...
The circadian clock regulates tissue homeostasis through temporal control of tissue-specific clock-controlled genes. In articular cartilage, disruptions in the are linked to a procatabolic state. presence inflammation, cartilage is disrupted, which further contributes pathogenesis diseases such as osteoarthritis. Using synthetic biology and engineering, we developed tested genetically engineered from murine induced pluripotent stem cells (miPSCs) capable preserving inflammation. We found...
ObjectiveCartilage in joints such as the hip and knee experiences repeated phases of heavy loading low load recovery during 24-h day/night cycle. Our previous work has shown 24 h rhythmic changes gene expression at transcript level between night day wild type mouse cartilage which is lost a circadian clock knock-out model. However, it remains unknown to what extent rhythms also regulate protein this matrix rich tissue.MethodsWe investigated daily abundance femoral head articular by...
Abstract The circadian clock in mammals temporally coordinates physiological and behavioural processes to anticipate daily rhythmic changes their environment. Chronic disruption rhythms (e.g., through ageing or shift work) is thought contribute a multitude of diseases, including degeneration the musculoskeletal system. intervertebral disc (IVD) spine contains clocks which control ∼6% transcriptome manner, key genes involved extracellular matrix (ECM) homeostasis. However, it remains largely...
The Golgi complex comprises a connected ribbon of stacked cisternal membranes localized to the perinuclear region in most vertebrate cells. position and morphology this organelle depends upon interactions with microtubules actin cytoskeleton. In contrast, we know relatively little about relationship intermediate filaments (IFs). study, show that is close physical proximity vimentin IFs cultured mouse human We also trans-Golgi network coiled-coil protein GORAB can physically associate IFs....
Kidney physiology shows diurnal variation, and a disrupted circadian rhythm is associated with kidney disease. However, it remains largely unknown whether glomeruli, the filtering units in kidney, are under control. Here, we investigated core clock components together their rhythmic targets modes of regulation. With gene reporter mice, cell-autonomous glomerular clocks which likely govern fluctuations were identified. Using time-series transcriptomic profiling, first transcriptome 375...
Abstract Objectives Articular cartilage undergoes cyclical heavy loading and low load recovery during the 24-hour day/night cycle. We investigated daily changes of protein abundance in mouse femoral head articular by performing time-series proteomics study. Methods Tandem mass spectrometry analysis was used to quantify proteins extracted from cartilage. Bioinformatics performed rhythmic abundance. Primary chondrocytes were isolated cultured for independent validation selected proteins....
Objective: Prior studies have shown that disruption of the circadian clock leads to cartilage degeneration in mice while shift work is associated with higher risk osteoarthritis (OA) humans. In this study we investigated potential heat pulses restore dampened rhythms articular cartilage. Methods: Femoral head explants and primary chondrocytes were isolated from PER2::LUC mice. Human femoral condyle was obtained osteoarthritic patients undergoing total knee replacement. Tissues cells exposed...
Abstract Daily rhythms in mammalian behaviour and physiology are generated by a multi-oscillator circadian system entrained through environmental cues (e.g. light). Presence of niche-dependent physiological time has been proposed, allowing local tissues flexibility phase adjustment. However, to date, such stimuli have remained elusive. Here we show that cycles mechanical loading osmotic within range drive rhythmic expression clock genes reset amplitude cartilage intervertebral disc tissues....
Abstract Objective Mutations in the catalytic site of ubiquitin-fold modifier 1(UFM1)-specific peptidase 2 (UFSP2) gene have been identified to cause autosomal dominant Beukes hip dysplasia a large multigenerational family and novel form spondyloepimetaphyseal second family. We investigated expression UFSP2/UFM1 system during mouse joint development connection ER stress induced osteogenic differentiation. Methods The pattern Ufsp2 was determined by radioactive RNA situ hybridisation on...