A5045749767- Genetic and Kidney Cyst Diseases
- Hedgehog Signaling Pathway Studies
- Epigenetics and DNA Methylation
- Genetic Syndromes and Imprinting
- Genomics and Chromatin Dynamics
- Renal and related cancers
- Developmental Biology and Gene Regulation
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- MicroRNA in disease regulation
- Congenital heart defects research
- Cancer-related molecular mechanisms research
- RNA Interference and Gene Delivery
- Congenital limb and hand anomalies
- Animal Genetics and Reproduction
- RNA Research and Splicing
- Microtubule and mitosis dynamics
- Pancreatic and Hepatic Oncology Research
- Protist diversity and phylogeny
- Nanoplatforms for cancer theranostics
- Nuclear Structure and Function
- Congenital Ear and Nasal Anomalies
- Phytase and its Applications
- Retinoids in leukemia and cellular processes
- Photosynthetic Processes and Mechanisms
- Lipid metabolism and biosynthesis
University of Oxford
2018-2020
Science Oxford
2020
Memorial Sloan Kettering Cancer Center
2014-2017
Kettering University
2012
University of Bath
2009-2011
Wellcome Trust
2006
University of Dundee
2006
The chicken talpid(3) mutant, with polydactyly and defects in other embryonic regions that depend on hedgehog (Hh) signalling (e.g. the neural tube), has a mutation KIAA0568. Similar phenotypes are seen mice human syndromes mutations genes encode centrosomal or intraflagella transport proteins. Such lead to primary cilia, sites where Hh occurs. Here, we show cells of mutant embryos lack cilia can be rescued constructs encoding Talpid3. also develop polycystic kidneys, consistent widespread...
Talpid 3 is a classical chicken mutant with abnormal limb patterning and malformations in other regions of the embryo known to depend on Hedgehog signaling. We combined ease manipulating embryos emerging knowledge genome reveal directly basis defective signal transduction talpid identify gene. show several that phenotype completely ligand independent demonstrate for first time absolutely required function both Gli repressor activator intracellular pathway. map locus chromosome 5 find...
Defects in long-range regulatory elements have recently emerged as previously underestimated factors the genesis of human congenital disorders. Léri-Weill dyschondrosteosis is a dominant skeletal malformation syndrome caused by mutations short stature homeobox gene SHOX . We analysed four families with deletions pseudoautosomal region but still an intact coding region. Using fluorescence situ hybridization and single nucleotide polymorphism studies, we identified interval ∼200 kb that was...
Sonic hedgehog signalling is essential for the embryonic development of many tissues including central nervous system, where it controls pattern cellular differentiation. A genome-wide screen neural progenitor cells to evaluate Shh signalling-regulated transcriptome identified forkhead transcription factor Foxj1. In both chick and mouse Foxj1 expressed in ventral midline tube that make up floor plate. Consistent with role formation long motile cilia, plate produce cilia are longer than...
Specification of digit number and identity is central to pattern in vertebrate limbs. The classical talpid(3) chicken mutant has many unpatterned digits together with defects other regions, depending on hedgehog (Hh) signalling, exhibits embryonic lethality. a mutation KIAA0586, which encodes centrosomal protein required for the formation primary cilia, are sites Hh signalling. highly conserved exons 11 12 KIAA0586 essential rescue cilia mutants. We constitutively deleted these two make...
The importance of primary cilia in human health is underscored by the link between ciliary dysfunction and a group primarily recessive genetic disorders with overlapping clinical features, now known as ciliopathies. Many proteins encoded ciliopathy-associated genes are components handful multi-protein complexes important for transport cargo to basal body and/or into cilium. A key question whether different cooperate formation, they participate cilium assembly conjunction intraflagellar (IFT)...
The zinc-finger transcription factor GLI3 is an important mediator of Sonic hedgehog signaling and crucial for patterning many aspects the vertebrate body plan. In vertebrates, mechanism SHH signal transduction its action on target genes by means activating or repressing forms have been studied most extensively during limb development specification central nervous system. From these studies it has emerged, that Gli3 expression must be subject to a tight spatiotemporal regulation. However,...
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths worldwide, but has a 5-year survival rate only 7% primarily due to late diagnosis and ineffective therapies. To treat or even prevent PDAC, it vital that we understand initiating events lead tumour onset. PDAC develops from preneoplastic lesions, most commonly pancreatic intraepithelial neoplasias (PanINs), driven by constitutive activation KRAS. In patients, PanINs are associated with regions...
Abstract Sonic hedgehog (Shh) signalling controls integrated specification of digit pattern and growth in the chick wing but downstream gene networks remain to be unravelled. We analysed 3D expression patterns genes encoding cell cycle regulators using Optical Projection Tomography. Hierarchical clustering spatial matrices revealed a dorsal layer bud, which almost all were expressed, that positive had similar while those N‐myc CyclinD2 distinct closely related. compared these computationally...
740 Background: SCALOP was a multi-centre phase II RCT where 114 patients with LAPC were received 3 cycles of Gemcitabine and Capecitabine (GEMCAP) those stable/responding disease (n = 74) randomised to Gem-RT or Cap-RT. The trial showed superiority Baseline blood samples analysed for 35 circulating biomarkers. In vivo study undertaken candidate biomarker (CCL5) test actionability. Methods: Patient bloods tested using R&D multiplexed magnetic Luminex assays IGF-1, TGF-b1 b-NGF DuoSet...
Bardet-Biedl syndrome (BBS )a nd Meckel-Gruber (MKS) are genetic disorders caused by disruption of primary cilia. The BBS and MKS proteins found in two distinct protein complexes but the functional relationships between these not clear. Here we analyze double mutant mouse embryos to define relationships. Bbs4;Mks1 show a stronger phenotype than either single mutant, with completely penetrant micropthalmia polydactyly, loss ventral neural cell types, reduced number short bulbous This additive...
Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer with poor survival outcomes. Results from clinic have demonstrated lack efficacy when either radiotherapy (RT) or immunotherapy are used as a monotherapy. Recent publications revealed synergistic effect on RT-induced immune modulation and reduced suppression was administrated concurrently RT in mouse models. Other demonstrate that evasion PDAC depends CCL5/CCR5 axis to recruit...
Abstract Acinar-to-ductal metaplasia (ADM) is a homeostatic mechanism where in response to inflammation for example during pancreatitis, acini dedifferentiate, adopting progenitor-like cell fate before proliferating and redifferentiating regenerate the pancreas. In pancreatic ductal adenocarcinoma (PDAC) constitutive activation of KRas promotes ADM; however, redifferentiation blocked instead cells are locked an irreversible duct-like state leading neoplastic transformation PanIN formation....