A5048627847- CRISPR and Genetic Engineering
- Immune Response and Inflammation
- Parasites and Host Interactions
- Asthma and respiratory diseases
- IL-33, ST2, and ILC Pathways
- bioluminescence and chemiluminescence research
- Pluripotent Stem Cells Research
- Neuroinflammation and Neurodegeneration Mechanisms
- interferon and immune responses
- Immune cells in cancer
- Neonatal Health and Biochemistry
- Mast cells and histamine
- Helminth infection and control
- Immune Cell Function and Interaction
- Erythrocyte Function and Pathophysiology
- Dermatology and Skin Diseases
- Allergic Rhinitis and Sensitization
- Immunotherapy and Immune Responses
- Heme Oxygenase-1 and Carbon Monoxide
- Parasitic Diseases Research and Treatment
- RNA and protein synthesis mechanisms
- Inflammasome and immune disorders
- Cytokine Signaling Pathways and Interactions
- Blood properties and coagulation
- NF-κB Signaling Pathways
European Molecular Biology Laboratory
2020-2025
University of Manchester
2010-2023
Cancer Research UK Scotland Institute
2022
Manchester Academic Health Science Centre
2017-2020
Wythenshawe Hospital
2017
Manchester University NHS Foundation Trust
2017
Epistem (United Kingdom)
2005
Syngenta (United Kingdom)
2003-2005
University of California, Irvine
2005
Syngenta (Switzerland)
2003
The functional integrity of the intestinal epithelial barrier forms a major defense against invading pathogens, including gastrointestinal-dwelling nematodes, which are ubiquitous in their distribution worldwide. Here, we show that an increase rate cell turnover large intestine acts like "epithelial escalator" to expel Trichuris and movement is under immune control by cytokine interleukin-13 chemokine CXCL10. This host protective mechanism pathogens has implications for our wider...
Abstract IL-33 (IL-1F11) binds ST2 (IL-1R4), both of which are associated with optimal CD4+ Th2 polarization. Exogenous drives induction Th2-associated cytokines and pathological changes within the gut mucosa. polarization is also a prerequisite to expulsion intestinal-dwelling nematode Trichuris muris. In this study, we demonstrate that mRNA expressed early during parasite infection susceptible mice can be induced expel by regime exogenous administration. prevents an inappropriate...
Abstract Two prominent concepts for the sensing of shear stress by endothelium are PIEZO1 channel as a mediator mechanically activated calcium ion entry and PECAM1 cell adhesion molecule apex triad with CDH5 VGFR2. Here, we investigated if there is relationship. By inserting non-disruptive tag in native mice, reveal situ overlap PECAM1. Through reconstitution high resolution microscopy studies show that interacts directs it to cell-cell junctions. extracellular N-terminus critical this, but...
Abstract The gut microbiota operates at the interface of host–environment interactions to influence human homoeostasis and metabolic networks 1–4 . Environmental factors that unbalance microbial ecosystems can therefore shape physiological disease-associated responses across somatic tissues 5–9 However, systemic impact microbiome on germline—and consequently F 1 offspring it gives rise to—is unexplored 10 Here we show act as a key between paternal preconception environment intergenerational...
Abstract Murine studies have demonstrated that, as with other nematodes, infection the intestinal nematode Trichinella spiralis is associated a pronounced mastocytosis, eosinophilia and an elevation in serum levels of total IgE. Both interleukin (IL)‐4 IL‐5 are clearly important generation IgE responses eosinophilia, respectively, but control mucosal mastocytosis vivo not well defined. Mucosal mast cells appear to be particularly regard T. infections there good evidence suggest their...
Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine, mainly expressed by epithelial cells, and key to the development of allergic responses. The well-documented involvement TSLP in allergy has led conviction that promotes inflammatory Th2 cell However, we now report interaction with its receptor (TSLPR) no functional impact on protective immune responses after infection 2 helminth pathogens, Heligmosomoides polygyrus Nippostrongylus brasiliensis . Mice deficient...
Infection and systemic inflammation are risk factors for cerebrovascular diseases poststroke infections impair outcome in stroke patients, although the mechanisms of their contribution mostly unknown. No preclinical studies have identified how chronic infection affects ischemic brain damage which key inflammatory mediators involved. We used a well established model gut ( Trichuris muris ) to study contributes injury. show that, mice, that leads Th1-polarized immune response dramatically...
CRISPR-Cas9 gene-editing technology has facilitated the generation of knockout mice, providing an alternative to cumbersome and time-consuming traditional embryonic stem cell-based methods. An earlier study reported up 16% efficiency in generating conditional (cKO or floxed) alleles by microinjection 2 single guide RNAs (sgRNA) single-stranded oligonucleotides as donors (referred herein "two-donor floxing" method).We re-evaluate two-donor method from a consortium 20 laboratories across...
Abstract The proliferation, differentiation, and survival of cells the mononuclear phagocyte system (MPS; progenitors, monocytes, macrophages, classical dendritic cells) are controlled by signals from M-CSF receptor (CSF1R). Cells MPS lineage have been identified using numerous surface markers transgenic reporters, but none is both universal restricted. In this article, we report development characterization a CSF1R reporter mouse. A FusionRed (FRed) cassette was inserted in-frame with C...
The reversible glycosylation of nuclear and cytoplasmic proteins (O-GlcNAcylation) is catalyzed by a single enzyme, namely O-GlcNAc transferase (OGT). mammalian Ogt gene X-linked, it essential for embryonic development the viability proliferating cells. We perturbed OGT’s function in vivo creating murine allelic series four amino acid substitutions, reducing catalytic activity to range degrees. severity lethality was proportional extent impairment catalysis, demonstrating that modification...
Production of neutralizing anti-IL-9 antibodies was induced in mice by immunization with mouse IL-9 coupled to ovalbumin. In the six strains tested, a strong and long-lasting response developed seric inhibitory titers 10 −3 −5 , as measured an vitro IL-9-dependent cell proliferation assay. vivo this completely abrogated increase mast-cell protease-1 levels well eosinophilia observed after implantation IL-9-secreting tumor. We took advantage method assess role infections nematode Trichuris...
In vivo manipulation of cytokine and/or receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility associated a T helper cell type 1 (Th1) response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) signaling anti–TNF-α monoclonal antibody treatment, we have extended these studies reveal critical role for TNF-α regulation Th2 cytokine–mediated host...
Immune responses associated with intestinal nematode infections are characterized by the activation of T-helper 2 (Th2) cells. Previous studies demonstrated that during Trichinella spiralis infection, Th2 cells contribute to development muscle hypercontractility and worm eviction from gut, in part through signal transducer activator transcription factor 6 (Stat6). Interleukin-9 (IL-9), a Th2-cell-derived cytokine, has pleiotropic activities on various not mediated Stat6. In this study, we...
Secreted and membrane-bound proteins, which account for 1/3 of all play critical roles in heart health disease. The endoplasmic reticulum (ER) is the site synthesis, folding, quality control these proteins. Loss ER homeostasis function underlies pathogenesis many forms disease.To investigate mechanisms responsible regulating cardiac function, to explore therapeutic potentials strengthening treat disease.Screening a range signaling molecules led discovery that Pak (p21-activated kinase)2...
It has been hypothesized that IL-1α is released from damaged cardiomyocytes following myocardial infarction (MI) and activates cardiac fibroblasts via its receptor (IL-1R1) to drive the early stages of remodeling. This study aimed definitively test this hypothesis using cell type–specific IL-1R1–KO mouse models. A floxed Il1a was created used generate a cardiomyocyte-specific IL-1α–KO (MIL1AKO) line. tamoxifen-inducible fibroblast-specific IL-1R1 hemizygous KO (FIL1R1KO) line also generated....
Abstract IL-13 is a Th2-derived cytokine associated with pathological changes in asthma and ulcerative colitis. Moreover, it plays major role the control of gut nematode infection immunopathology. The current paradigm that these effects are due to T cell-derived IL-13. We show this study an innate source IL-13, intraepithelial NK cell, responsible for disruption intestinal tissue architecture induction goblet cell hyperplasia characterizes helminth Trichinella spiralis. or IL-4Rα (but not...
Stroke induces a systemic response that involves rapid activation of inflammatory cascades, followed later by immunodepression. Experimental stroke-induced responses in the bone marrow, which is primary source circulating monocytes and granulocytes, have not been investigated previously. We show cerebral ischaemia induced early (4 hours) release CXCR2-positive granulocytes from was associated with upregulation CXCL1 (a ligand for CXCR2) granulocyte-colony-stimulating factor, key cytokine...
Vascular smooth muscle turnover has important implications for blood vessel repair and the development of cardiovascular diseases, yet lack specific transgenic animal models prevented it's in vivo analysis.The objective this study was to characterize dynamics mechanisms vascular from earliest stages embryonic arterial adult.We show that CD146 is transiently expressed development. By using CRISPR-Cas9 genome editing vitro differentiation assay, we demonstrate regulates balance between...
Fibrillin microfibrils are extracellular matrix assemblies that form the template for elastic fibres, endow blood vessels, skin and other tissues with extensible properties. They also regulate bioavailability of potent growth factors TGF-β superfamily. A disintegrin metalloproteinase thrombospondin motifs (ADAMTS)10 is an essential factor in fibrillin microfibril function. Mutations fibrillin-1 or ADAMTS10 cause Weill-Marchesani syndrome (WMS) characterized by short stature, eye defects,...
Significance The circadian clock protein REVERBα is proposed to be a key regulator of liver metabolism. We now show that action critically dependent on metabolic state. Using transgenic mouse models, we the true role buffer against aberrant responses perturbation, rather than confer rhythmic regulation programs lipid synthesis and storage, as has been thought previously. Thus, in case metabolism, does not so much drive processes, provide protection mistimed feeding cues. Understanding how...
The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. frequently associated with the damaging inflammation non-communicable disease states considered an attractive therapeutic target. However, there much regarding mechanism activation remains unknown. Chloride efflux suggested as important step in activation, but which chloride channels are involved still We used chemical, biochemical, genetic approaches...
Abstract Background & Aims PIEZO1 and TRPV4 are mechanically osmotically regulated calcium‐permeable channels. The aim of this study was to determine the relevance relationship these channels in contractile tone hepatic portal vein, which experiences mechanical osmotic variations as it delivers blood liver from intestines, gallbladder, pancreas spleen. Methods Wall tension measured freshly dissected veins adult male mice, were genetically unmodified or modified for either a...
The ontogeny and function of gut-associated-lymphoid tissue is known to be critically dependent on the β7 integrin subfamily. We have investigated development intestinal inflammation pathogen-specific protective immunity enteric helminth infection in knockout (KO) mice. During Trichinella spiralis small intestine there was a significant delay reduction magnitude eosinophilia mastocytosis absence integrin, resulting impaired host protection. Aberrant distribution mast cells also observed...