A5008731993- Epigenetics and DNA Methylation
- Amyotrophic Lateral Sclerosis Research
- Digestive system and related health
- Microtubule and mitosis dynamics
- Liver physiology and pathology
- Mechanisms of cancer metastasis
- Cancer-related gene regulation
- Neurogenetic and Muscular Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Wnt/β-catenin signaling in development and cancer
- Cancer, Hypoxia, and Metabolism
- Alzheimer's disease research and treatments
- Organ Transplantation Techniques and Outcomes
- Hepatocellular Carcinoma Treatment and Prognosis
- RNA modifications and cancer
- Gut microbiota and health
- Nutrition, Genetics, and Disease
- Pancreatic and Hepatic Oncology Research
- CRISPR and Genetic Engineering
- Cancer Genomics and Diagnostics
- Glioma Diagnosis and Treatment
- Telomeres, Telomerase, and Senescence
- Amino Acid Enzymes and Metabolism
- Cancer Cells and Metastasis
- MicroRNA in disease regulation
Cancer Research UK
2021-2025
University of Glasgow
2024-2025
Cancer Research UK Scotland Institute
2020-2024
German Center for Neurodegenerative Diseases
2013-2024
Cardiff University
2017-2022
Technische Universität Dresden
2017
University Hospital Carl Gustav Carus
2017
Liverpool John Moores University
2015
Ludwig-Maximilians-Universität München
2014
Unusual Aggregates Several recent papers have revealed the unexpected genetic and pathological overlap between frontotemporal lobar degeneration (FTLD) amyotrophic lateral sclerosis (ALS). The most common cause is GGGGCC hexanucleotide repeat expansion upstream of C9orf72 coding region affecting about 10% all patients. It currently unknown how might lead to neurodegeneration. patients show two distinct types ubiquitinated inclusions in central nervous system, one which was identified as...
Hexanucleotide repeat expansion in C9orf72 is the most common pathogenic mutation patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite lack of an ATG start codon, translated all reading frames into dipeptide (DPR) proteins, which form insoluble, ubiquitinated, p62-positive aggregates that are abundant cerebral cortex cerebellum. To specifically analyze DPR toxicity aggregation, we expressed proteins from synthetic genes containing a codon...
Abstract The liver has a unique ability to regenerate 1,2 ; however, in the setting of acute failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency transplantation as only curative option 3–5 . Here, advance understanding human regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling healthy and ALF explant livers generate single-cell, pan-lineage atlas regeneration. We uncover novel ANXA2 + migratory hepatocyte subpopulation, which...
Abstract Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause cancer-related mortality worldwide 1,2 . HCC occurs typically from background chronic disease, caused by spectrum predisposing conditions. Tumour development driven expansion clones that accumulate progressive driver mutations 3 , with hepatocytes likely cell origin 2 However, landscape in broadly independent underlying aetiologies 4 Despite an increasing range systemic treatment options...
A massive expansion of a GGGGCC repeat upstream the C9orf72 coding region is most common known cause amyotrophic lateral sclerosis and frontotemporal dementia. Despite its intronic localization lack canonical start codon, both strands are translated into aggregating dipeptide (DPR) proteins: poly-GA, poly-GP, poly-GR, poly-PR poly-PA. To address conflicting findings on predominant toxicity different DPR species in model systems, we compared expression pattern proteins rat primary neurons...
Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated cyan fluorescent protein (CFP). Transgenic progressively developed inclusions predominantly motoneurons interneurons spinal cord brain stem deep cerebellar nuclei. Poly-GA co-aggregated p62, Rad23b newly...
A repeat expansion in the non-coding region of C9orf72 gene is most common mutation causing frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Sense antisense transcripts are translated into aggregating dipeptide (DPR) proteins all reading frames (poly-GA,-GP,-GR,-PA -PR) through an unconventional mechanism. How these changes contribute to cytoplasmic mislocalization aggregation TDP-43 thereby ultimately leading neuron loss remains unclear. The RNA itself...
Cellular senescence is not only associated with ageing but also impacts physiological and pathological processes, such as embryonic development wound healing. Factors secreted by senescent cells affect their microenvironment can induce spreading of locally. Acute severe liver disease hepatocyte frequently progresses to multi-organ failure. Why the latter occurs poorly understood. Here we demonstrate in extrahepatic organs organ dysfunction response using injury models genetic...
Research Article28 March 2017Open Access Transparent process Antibodies inhibit transmission and aggregation of C9orf72 poly-GA dipeptide repeat proteins Qihui Zhou German Center for Neurodegenerative Diseases (DZNE), Munich, Germany Munich Cluster Systems Neurology (SyNergy), Search more papers by this author Carina Lehmer Meike Michaelsen Kohji Mori orcid.org/0000-0003-2629-0723 Biomedical Center, Biochemistry, Ludwig Maximilians-Universität München, Planegg-Martinsried, Department...
Mice are a widely used pre-clinical model system in large part due to their potential for genetic manipulation. The ability manipulate gene expression specific cells under temporal control is powerful experimental tool. liver central metabolic homeostasis and site of many diseases, making the targeting hepatocytes attractive. Adeno-associated virus 8 (AAV8) vectors valuable instruments manipulation hepatocellular expression. However, off-target effects mice have not been thoroughly explored....
Autophagy represses YAP/TAZ-dependent hepatocyte dedifferentiation into liver progenitor cells to prevent tumorigenesis.
The human gut microbiome is considered an organ in its entirety and has been the subject of extensive research due to role physiology, metabolism, digestion, immune regulation. Disequilibria normal have associated with development several gastrointestinal diseases, but exact underlying interactions are not well understood. Conventional vivo vitro modelling systems fail faithfully recapitulate complexity host–gut microbiome, emphasising requirement for novel that provide a platform study more...
Abstract The liver has a unique ability to regenerate 1,2 , however in the setting of acute failure (ALF) this regenerative capacity is often overwhelmed and emergency transplantation only curative option 3-5 . To advance our understanding human regeneration inform design pro-regenerative therapies, we use paired single-nuclei RNA sequencing (snRNA-seq) combined with spatial profiling healthy ALF explant livers generate first single-cell, pan-lineage atlas regeneration. We uncover novel...
Liver tumours, both primary and metastatic, are diseases of unmet clinical need. Hepatocellular carcinoma (HCC) the most common liver tumour, like many other cancers, may be treated by stereotactic ablative radiotherapy (SABR), reducing off-target effects radiation on local anatomical structures. However, integrating all necessary components for irradiation hepatocellular in murine models has not yet been reported. Here we provide development detailed characterisation a SABR model combining...
Mouse models of lineage tracing have helped to describe the important subpopulations hepatocytes responsible for liver regeneration. However, conflicting results been obtained from different models. Herein, we aimed reconcile these reports by repeating a key lineage-tracing study pericentral and characterising this Axin2CreERT2 model in detail.
Glutamine synthetase (GS) activity is conserved from prokaryotes to humans, where the ATP-dependent production of glutamine glutamate and ammonia essential for neurotransmission detoxification. Here, we show that mammalian GS uses methylamine produce a methylated analog, N
Abstract In addition to smoking and UV exposure, lifestyle factors, such as diet, nutrition, physical activity, have been shown play a significant role for many cancers. It is estimated that up 50% of some cancer types are preventable; through dietary changes with the presence or absence certain components strongly associated an increased decreased risk. Here we summarize work has performed polyphenols, focus on those derived from black raspberries. These extensively studied prevention...
Leukocyte cell-derived chemotaxin 2 (Lect2) is a chemokine-like chemotactic factor that has been identified as downstream target of the Wnt signalling pathway. Whilst primary function Lect2 thought to be in modulating inflammatory process, it recently implicated potential inhibitor Deregulation pathway, often due loss negative regulator APC, found ~80% colorectal cancer (CRC). Here we have used ApcMin/+Lect2-/- mouse model characterise role Wnt-driven intestinal tumourigenesis....
Abstract Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2 , which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies −/− mouse has been shown (1) be resistant intestinal tumourigenesis (2) have an enhanced inflammatory/immune response, observations that are inconsistent with links To clarify its inflammation, used constitutive conditional models of deletion explore epithelial non‐epithelial...