A5011301544- Lymphatic System and Diseases
- Genetic Neurodegenerative Diseases
- Allergic Rhinitis and Sensitization
- Cellular Mechanics and Interactions
- Immunotherapy and Immune Responses
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Muscle Physiology and Disorders
- Hippo pathway signaling and YAP/TAZ
- Peptidase Inhibition and Analysis
- Sirtuins and Resveratrol in Medicine
- Cell Adhesion Molecules Research
- Entomological Studies and Ecology
- Galectins and Cancer Biology
- Cancer Cells and Metastasis
- Wnt/β-catenin signaling in development and cancer
- Noise Effects and Management
- T-cell and B-cell Immunology
- Phosphodiesterase function and regulation
- Autophagy in Disease and Therapy
- Ubiquitin and proteasome pathways
- Endoplasmic Reticulum Stress and Disease
- Cardiomyopathy and Myosin Studies
- Cancer Genomics and Diagnostics
- Head and Neck Cancer Studies
MRC Laboratory for Molecular Cell Biology
2019-2022
University College London
2016-2022
UK Dementia Research Institute
2018
Huntington's Disease Association
2016
King's College London
2013-2016
Columbia University
2013
United States Congress
2013
Universidade Federal de Minas Gerais
2013
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
2013
Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It caused by CAG repeat expansion in exon 1 of the HTT gene translates to polyglutamine tract huntingtin protein (HTT). The formation fragments has been implicated as an essential step molecular pathogenesis HD several proteases cleave have identified. However, importance smaller N-terminal highlighted their presence...
Lymph nodes (LNs) act as filters, constantly sampling peripheral cues. This is facilitated by the conduit network, a tubular structure of aligned extracellular matrix (ECM) fibrils ensheathed fibroblastic reticular cells (FRCs). LNs undergo rapid 3- to 5-fold expansion during adaptive immune responses, but these ECM-rich structures are not permanently damaged. Whether flow or filtering function affected LN unknown. Here, we show that conduits partially disrupted acute expansion, FRC-FRC...
Abstract Emergent physical properties of tissues are not readily understood by reductionist studies their constituent cells. Here, we show molecular signals controlling cellular, physical, and structural collectively determine tissue mechanics lymph nodes, an immunologically relevant adult tissue. Lymph nodes paradoxically maintain robust architecture in homeostasis yet continually poised for extensive expansion upon immune challenge. We find that murine models challenge, cytoskeletal a...
Huntington's disease is caused by a CAG repeat expansion in exon 1 of the HTT gene. We have previously shown that does not always splice to 2 producing small transcript (HTTexon1) encodes highly pathogenic protein. The mechanisms which this incomplete splicing occurs are unknown. Here, we generated minigene system recapitulates repeat-length dependence HTTexon1 production, and has allowed us define regions intron necessary for splicing. show manipulation expression levels factor SRSF6,...
Neurodegenerative diseases, characterised by the progressive and selective neuronal death in central nervous system, are frequently accompanied an activated immune system. In Huntington's disease (HD), clinical animal studies show evidence of activity, along with hyper-reactive monocyte/macrophage responses, while application immunosuppressive regimens have imparted beneficial effects to HD mice. These findings suggest a contributory role system pathology, immune-based interventions offering...
Huntington's disease (HD) is a neurodegenerative disorder for which there are no disease-modifying treatments. SIRT1 NAD+-dependent protein deacetylase that implicated in maintaining neuronal health during development, differentiation and ageing. Previous studies suggested the modulation of activity neuroprotective HD mouse models, however, mechanisms controlling unknown. We have identified striatum-specific phosphorylation-dependent regulatory mechanism induction under normal physiological...
Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder of which skeletal muscle atrophy a common feature, and multiple lines evidence support muscle-based pathophysiology in HD mouse models. Inhibition myostatin signaling increases mass, therapeutic approaches based on this are clinical development. We have used soluble ActRIIB decoy receptor (ACVR2B/Fc) to test the effects myostatin/activin A inhibition R6/2 model HD. Weekly administration from 5 11 weeks age...
ABSTRACT In adaptive immunity, CLEC-2+ dendritic cells (DCs) contact fibroblastic reticular (FRCs) inhibiting podoplanin-dependent actomyosin contractility, permitting FRC spreading and lymph node expansion. The molecular mechanisms controlling remodelling are incompletely understood. We asked how podoplanin is regulated on FRCs in the early phase of expansion, which other proteins required for response to DCs. find that its partner CD44 CD9 differentially expressed by specific stromal...
Histone Deacetylase 11 (HDAC11) is highly expressed in the central nervous system where it has been reported to have roles neural differentiation. In contrast with previous studies showing nuclear and cytoplasmic localisation, we observed synaptic enrichment of HDAC11. Knockout mouse models for HDACs 1-9 important guiding development isoform specific HDAC inhibitors as effective therapeutics. Given close relationship between HDAC11 cells vitro, examined tissue a previously uncharacterised...
Melanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease. cells utilize amoeboid migration as mode of local invasion. Amoeboid invasion characterized by rounded cell morphology and high actomyosin contractility driven Rho GTPase signalling. Migrastatic drugs targeting actin polymerization are therefore a promising treatment option for melanoma. To predict potential, biomarkers functionally linked to pathways needed. The glycoprotein...
Lymph node expansion is pivotal for adaptive immunity. CLEC-2 + migratory dendritic cells (DCs) interact with fibroblastic reticular (FRCs) to inhibit podoplanin-dependent actomyosin contractility, permitting FRC spreading and lymph expansion. However, the molecular mechanisms controlling remodelling are not fully understood. We asked how podoplanin regulated on FRCs in early phase of vivo , further, which other markers required respond DCs. find that expression its partner proteins CD44 CD9...
Abstract Lymph nodes are uniquely organised niches for immune interactions. Fibroblastic reticular cells (FRCs) facilitate cell communication and regulate function by producing growth factors, chemokines inflammatory cues. Stromal expression of the glycoprotein Podoplanin (PDPN) is required lymph node development, but requirement PDPN signaling in FRCs adult has not been directly tested. Using a conditional vivo deletion model PDGFRα mGFPΔPDPN , scRNA-seq revealed that increased signalling...
<title>Abstract</title> Secondary lymphoid tissues develop specialized stromal networks to facilitate immune cell communication and efficient activation of adaptive immunity. This architecture is robust, maintaining topology throughout extensive remodelling tissue expansion in response challenge. We have previously reported that cytoskeletal mechanics the fibroblastic reticular (FRC) determine tension, increased tension initiates proliferation required for lymph node growth. However, it not...
Lymph nodes (LNs) work as filtering organs, constantly sampling peripheral cues. This is facilitated by the conduit network, a parenchymal tubular-like structure formed of bundles aligned extracellular matrix (ECM) fibrils ensheathed fibroblastic reticular cells (FRCs). LNs undergo 5-fold expansion with every adaptive immune response and yet these ECM-rich structures are not permanently damaged. Whether integrity functions affected during cycles LN resolution known. Here we show that...
Melanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease. cells utilise amoeboid migration as mode of local invasion. Amoeboid invasion characterized by rounded cell morphology and high actomyosin contractility driven the RhoA signalling pathway. Migrastatic drugs targeting actin polymerization to inhibit metastasis are therefore a promising treatment option. To predict potential, there need for biomarkers functionally linked pathways. The...
Dear Colleagues and Friends,We would like to congratulate the organizers of 2013 World Congress on Huntington's Disease (WCHD-13), being held between 15-18 September in Rio de Janeiro, Brazil, development an exciting congress program.This conference, a joint effort Federation Neurology (WFN) Research Group International Huntington Association (IHA), provides open forum for scientists, physicians, patients, families come together share their experiences, unique understanding, knowledge HD.We...
Abstract Emergent physical properties of tissues are not readily understood by reductionist studies their constituent cells. Here, we show molecular signals controlling cellular properties, collectively determining tissue mechanics lymph nodes, an immunologically-relevant, adult mammalian tissue. Lymph nodes paradoxically maintain robust architecture in homeostasis yet continually poised for extensive expansion upon immune challenge. We find that following challenge, cytoskeletal a meshwork...
Abstract Emergent physical properties of tissues are not readily understood by reductionist studies their constituent cells. Here, we show molecular signals controlling cellular properties, collectively determining tissue mechanics lymph nodes, an immunologically-relevant, adult mammalian tissue. Lymph nodes paradoxically maintain robust architecture in homeostasis yet continually poised for extensive expansion upon immune challenge. We find that following challenge, cytoskeletal a meshwork...
Huntington's disease is caused by a CAG repeat expansion in exon 1 of the HTT gene. We have previously shown that does not always splice to 2 producing small transcript (HTTexon1) encodes highly pathogenic protein. The mechanisms which this incomplete splicing occurs are unknown. Here, we generated novel minigene system recapitulates repeat-length dependence HTTexon1 production, and has allowed us define regions intron necessary for splicing. show manipulation expression levels factor SRSF6,...
Lymph nodes (LNs) act as filters, constantly sampling peripheral cues. This is facilitated by the conduit network, a tubular structure of aligned extracellular matrix (ECM) fibrils ensheathed fibroblastic reticular cells (FRCs). LNs undergo 3-5-fold expansion during each adaptive immune response but these ECM-rich structures are not permanently damaged. Whether integrity and filtering function affected LN unknown. Here we show that conduits disrupted acute FRC-FRC contacts remain connected....
<h3>Background</h3> N-terminal fragments of the mutant huntingtin (HTT) protein aggregate into oligomeric and fibrillary structures that can be detected as polyubiquitylated inclusion bodies in tissue sections from HD patients mouse models HD. Misfolded aggregated proteins are degraded through two main intracellular clearance systems, ubiquitin–proteasome system (UPS) autophagy–lysosome pathway. p62 is an adapter regulates proteolysis ubiquitylated via selective autophagy. In both R6/2...
<h3>Background</h3> We have previously shown that the <i>HTT</i> gene is incompletely spliced to generated a small exon 1 – intron polyadenylated mRNA translated produce an HTT protein. This occurs in all knock-in mouse models of HD, YAC128 mice, BACHD mice and patient tissues. Through bioinformatics, we predicted splicing factor SRSF6 binds degenerative motif includes both (CAG)n (CAGCAA)n sequences proposed ectopic recruitment related this aberrant event. <h3>Aims</h3> To compare effect...