A5083144603- Cancer, Lipids, and Metabolism
- interferon and immune responses
- Peroxisome Proliferator-Activated Receptors
- Cancer, Hypoxia, and Metabolism
- Metabolomics and Mass Spectrometry Studies
- Zebrafish Biomedical Research Applications
- RNA Research and Splicing
- RNA modifications and cancer
- Amyotrophic Lateral Sclerosis Research
- RNA and protein synthesis mechanisms
- Neurogenetic and Muscular Disorders Research
- RNA regulation and disease
- Epigenetics and DNA Methylation
- Invertebrate Immune Response Mechanisms
- Intracerebral and Subarachnoid Hemorrhage Research
- CRISPR and Genetic Engineering
- Immune Cell Function and Interaction
- Aquaculture disease management and microbiota
- Virus-based gene therapy research
- MicroRNA in disease regulation
- Genetic Neurodegenerative Diseases
- Protein Degradation and Inhibitors
- Lipid metabolism and biosynthesis
- Neuroinflammation and Neurodegeneration Mechanisms
- Developmental Biology and Gene Regulation
Institute of Genetics and Cancer
2020-2023
Medical Research Council
2020-2023
University of Edinburgh
2020-2023
University of Manchester
2015-2022
Edinburgh Cancer Research
2022
Macquarie University
2014-2021
Edinburgh College
2020
Manchester Academic Health Science Centre
2018-2019
Robert Bosch (Australia)
2014
The University of Sydney
2014
Microglia are specialized phagocytes in the vertebrate central nervous system (CNS). As resident immune cells of CNS they play an important role removal dying neurons during both development and several neuronal pathologies. have been shown to prevent diffusion damaging degradation products by engulfment ingestion. Here we describe a live imaging approach that uses UV laser ablation selectively stress kill spinal visualize clearance remnants microglia zebrafish cord. In vivo confirmed motile...
Transactivating DNA-binding protein-43 (TDP-43) deposits represent a typical finding in almost all ALS patients, more than half of FTLD patients and with several other neurodegenerative disorders. It appears that perturbation nucleo-cytoplasmic transport is an important event these conditions but the mechanistic role fate TDP-43 during neuronal degeneration remain elusive. We have developed experimental system for visualising perturbed nucleocytoplasmic at single-cell level vivo using...
Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome translation initiation are deleterious to development underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe novel zebrafish mutant, titania (ttis450), which harbours recessive lethal mutation pwp2h, gene encoding protein component the small subunit processome. The biochemical impacts this lesion decreased production mature 18S rRNA molecules, activation Tp53, impaired...
Currently there is a lack in fundamental understanding of disease progression most neurodegenerative diseases, and, therefore, treatments and preventative measures are limited. Consequently, great need for adaptable, yet robust model systems to both investigate elementary mechanisms discover effective therapeutics. We have generated Tol2 Gateway-compatible toolbox study disorders zebrafish, which includes promoters astrocytes, microglia motor neurons, multiple fluorophores, compatibility the...
Mucosal surfaces such as fish gills interface between the organism and external environment are major sites of foreign Ag encounter. In gills, balance inflammatory responses to waterborne pathogens regulatory toward commensal microbes is critical for effective barrier function overall health. mammals, IL-4 IL-13 in concert with IL-10 essential balancing immune suppressing inflammation. Although considerable progress has been made field immunology recent years, whether counterparts these key...
Dysregulated cellular metabolism is a cancer hallmark for which few druggable oncoprotein targets have been identified. Increased fatty acid (FA) acquisition allows cells to meet their heightened membrane biogenesis, bioenergy, and signaling needs. Excess FAs are toxic non-transformed but surprisingly not cells. Molecules underlying this adaptation may provide alternative drug targets. Here, we demonstrate that diacylglycerol O-acyltransferase 1 (DGAT1), an enzyme integral triacylglyceride...
FUS mutations can occur in familial amyotrophic lateral sclerosis (fALS), a neurodegenerative disease with cytoplasmic inclusion bodies motor neurons. To investigate pathology, we generated transgenic zebrafish expressing GFP-tagged wild-type or fALS (R521C) human FUS. Cell cultures were made from these and the subcellular localization of generation stress granule (SG) inclusions examined different cell types, including differentiated We demonstrate that mutant is mislocalized nucleus to...
Abstract Alterations in lipid metabolism cancer cells impact cell structure, signaling, and energy metabolism, making a potential diagnostic marker therapeutic target. In this study, we combined PET, desorption electrospray ionization-mass spectrometry (DESI-MS), nonimaging MS, transcriptomic analyses to interrogate changes transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected melanoma tumor nodules by PET using the...
Abstract In response to infection and injury, the neutrophil population rapidly expands then quickly re-establishes basal state when inflammation resolves. The exact pathways governing neutrophil/macrophage lineage outputs from a common granulocyte-macrophage progenitor are still not completely understood. From forward genetic screen in zebrafish, we identify transcriptional repressor, ZBTB11, as critical for emergency granulopoiesis. ZBTB11 sits pathway directly downstream of master myeloid...
ABSTRACT Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using hybrid positional cloning and next generation sequencing approach, identified mutations the nuclear localisation signal (NLS) T-box transcription factor 4 (Tbx4) impair protein, resulting altered gene expression patterns during development failure development....
RAS GTPases are frequently mutated in human cancer. H- and NRAS isoforms distributed over both plasma-membrane endomembranes, including the Golgi complex, but how this organizational context contributes to cellular transformation is unknown. Here we show that at selectively activated by apoptogenic stimuli antagonizes cell survival suppressing ERK activity through induction of PTPRκ, which targets CRAF for dephosphorylation. Consistently, contrast what occurs plasma-membrane, cannot induce...
Abstract Biallelic mutations in SNORD118 , encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given difficulty interpreting functional consequences of variants nonprotein genes, high allelic polymorphism across controls, we set out to provide a description molecular pathology clinical spectrum observed cohort patients LCC. We identified 64 affected individuals from 56 families. Age at presentation varied 3 weeks 67 years, disease onset after...
Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology incomplete. Spontaneous cerebral bleeding characteristic the human that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models associated several advantages, including high fecundity, optical translucency non-protected status prior 5 days post-fertilisation. Furthermore,...
<ns4:p>Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology incomplete. Spontaneous cerebral bleeding characteristic the human that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models associated several advantages, including high fecundity, optical translucency non-protected status prior 5 days post-fertilisation....
RNA homodimerization is important for various physiological processes, including the assembly of membraneless organelles, subcellular localization, and packaging viral genomes. However, understanding dimerization has been hampered by lack systematic in vivo detection methods. Here, we show that CLASH, PARIS, other proximity ligation methods detect homodimers transcriptome-wide as “overlapping” chimeric reads contain more than one copy same sequence. Analyzing published data sets, RNA:RNA...
Aicardi-Goutières syndrome (AGS1-9) is a genetically determined encephalopathy that falls under the type I interferonopathy disease class, characterized by excessive interferon (IFN-I) activity, coupled with upregulation of IFN-stimulated genes (ISGs), which can be explained vital role these proteins play in self-non-self-discrimination. To date, few mouse models fully replicate vast clinical phenotypes observed AGS patients. Therefore, we investigated use zebrafish as an alternative species...
Abstract Amyotrophic lateral sclerosis (ALS) is a form of motor neuron disease (MND) that characterized by the progressive loss neurons within spinal cord, brainstem, and cortex. Although ALS clinically manifests as heterogeneous disease, with varying onset survival, unifying feature presence ubiquitinated cytoplasmic protein inclusion aggregates containing TDP-43. However, precise mechanisms linking inclusions aggregation to neuronal are currently poorly understood. Bimolecular fluorescence...
Melanoma is the deadliest form of skin cancer; a primary driver this high level morbidity propensity melanoma cells to metastasize. When malignant tumours develop distant metastatic lesions new local tissue niche known impact on biology cancer cells. However, little about how different sites frontline targeted therapies. Intriguingly, bone have significantly lower response BRAF or MEK inhibitor Here, we investigated cellular can support by stimulating growth and survival via paracrine...
Abstract Healthy fish stocks are central to global food security. Key health is robust immunity at mucosal surfaces, and especially the gills. However, a balance must be struck between tolerating commensal microorganisms reacting appropriately toward pathogens. In mammals, IL-4 IL-13 in concert with IL-10 essential for balancing immune response pathogens suppressing inflammation. Whether their counterparts perform similar roles an open question. Here, we have generated IL-4/13A IL-4/13B...
ABSTRACT Dysregulated cellular metabolism is a hallmark of cancer. As yet, few druggable oncoproteins directly responsible for this have been identified. Increased fatty acid acquisition allows cancer cells to meet their membrane biogenesis, ATP, and signaling needs. Excess acids suppress growth factor cause oxidative stress in non-transformed cells, but surprisingly not cells. Molecules underlying adaptation may provide new drug targets. Here, we identify Diacylglycerol O-acyltransferase 1...
Abstract How mutations in the non-coding U8 snoRNA cause neurological disorder leukoencephalopathy with calcification and cysts (LCC) is poorly understood. We report first vertebrate mutant animal model for interrogating LCC-associated pathology. Mutant zebrafish exhibit defective central nervous system development ribosomal RNA (rRNA) biogenesis, tp53 activation which monitors ribosome biogenesis. Importantly, LCC patient fibroblasts demonstrate rRNA processing defects. Human precursor-U8...