Research
Regulation of Gene Expression in the Brain
CURRENT RESEARCH
The non-coding genome orchestrates chromatin structure and function. It responds to environmental challenges to modulate cellular phenotypes at several levels, including epigenetic, transcriptional, and post-transcriptional mechanisms. Many CNS disorders are caused by these gene & environment interactions, whereby a strong genetic component magnifies the effect of the environmental insult. The importance of non-coding DNA in driving CNS diseases is captured by the identification of numerous polymorphic domains in non-coding DNA being significantly associated with risk and progression for many conditions including our current focus on Motor Neuron and Parkinson’s Disease.
We have initiated the characterisation of how signalling pathways interact with such genetic variants resulting in differential changes in the cell's transcriptome which underlie a specific CNS disorder or mental health problem. Such analysis is byzantine, many variants are in non-coding DNA and can be located 100,000s of bases from the gene(s) they regulate and the environmental challenges can be pharmacological, physiological or psychological. We therefore integrate a wealth of bioinformatic and genetic data to delineate key regions of the genome involved in a particular cellular process. We then apply a rigorous set of molecular and biochemical protocols to validate our models. This methodology has been applied to mechanistically understand how a variety of neuropsychiatric and neurological conditions progress. Our current studies build upon a body of work explaining the role of repetitive DNA as both risk factors for CNS disorders and their action as transcriptional regulatory domains. This has facilitated our most recent studies of retrotransposons. Retrotransposons are considered to be activated and indeed mobilised in a number of age-related diseases and our current focus is their role in neurodegeneration. Our publication record demonstrates that these elements are key modifiers of risk for, severity and progression of Motor Neuron and Parkinson's disease.
This research in addition to adding to the basic understanding of how these diseases progress, it will also give insights into therapeutic windows for intervention. For example, the translational importance of retrotransposons for Motor Neuron Disease is highlighted by the Lighthouse study which is an open-label, multi-centre study to investigate the safety and tolerability of Triumeq, a combination anti-retroviral therapy (dolutegravir, abacavir, and lamivudine) for those with Motor Neuron Disease.
Research groups
Research grants
Validation of a new SNP-based patient stratification pipeline
MOTOR NEURONE DISEASE ASSOCIATION (UK)
April 2023 - September 2023
Provision of a MassArray Mass-spectrometry based multiplex genotyping platform (Agena Biosciences).
MEDICAL RESEARCH COUNCIL
July 2023 - June 2025
Motor Neuron Disease Genetic Risk Factors
THE DARBY RIMMER MND FOUNDATION (UK)
May 2022 - April 2025
From Biology to Quality of Life in Motor Neuron Disease
THE DARBY RIMMER MND FOUNDATION (UK)
May 2021 - April 2022
Bench Fees for Abdullah Meshal A Alsufyani
ROYAL EMBASSY OF SAUDI ARABIA CULTURAL BUREAU IN LONDON (UK)
March 2020 - August 2024
Wellcome Trust Four-Year PhD Studentship Programme
WELLCOME TRUST (UK)
October 2017 - March 2022
Retrotransposon mobilisation in Pain
PAIN RELIEF FOUNDATION (UK)
October 2016 - September 2019
Wellcome Trust Four-Year PhD Studentship with the Cellular and Molecular Physiology PhD Programme
WELLCOME TRUST (UK)
October 2015 - September 2019
Andrzej Wlodarski Memorial Research Fund in Motor Neurone Disease
PRIVATE INDIVIDUAL (UK)
September 2016 - August 2026
The role of the activity of endogenous transposable elements in the pathogenesis of ALS
MOTOR NEURONE DISEASE ASSOCIATION
November 2015 - October 2018
Effects of Acute Ischaemia on Thalamocortical Synaptic Transmission, in vitro.
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL
September 2000 - April 2004
Four year PhD programme in Cellular and Molecular Physiology.
WELLCOME TRUST (UK)
October 2005 - September 2009
Development of a mouse trigeminal pain model
PAIN RELIEF FOUNDATION (UK)
April 2007 - October 2007
Application of automated, high-content, live-cell, fluorescence imaging in multidisciplinary studies of epithelial, neuronal and stem cell function.
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL
April 2007 - March 2008
High resolution analysis of phenotype in manipulated complex tissues.
THE CARDIOTHORACIC CENTRE (UK)
April 2003 - April 2004
Delivery of artificial chromosomes in vivo via a virus vector system.
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL
November 2001 - November 2003
Exploitation of Genome Wide Association Biomarkers for Cognitive Decline
MEDICAL RESEARCH COUNCIL
April 2013 - December 2013
Winter Neuropeptide Conference
ROYAL SOCIETY (CHARITABLE)
February 2009
High resolution analysis of phenotype in manipulated complex tissues.
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL
November 2003 - November 2004
Transcriptional regulation mediated by polymorphic domains termed variable number tandem repeats.
WELLCOME TRUST (UK)
April 2001 - October 2003
Genetic predisposition to breast cancer
ROYAL LIVERPOOL AND BROADGREEN UNIVERSITY HOSPITALS NHS TRUST CHARITABLE FUNDS (UK)
January 2013 - December 2014
Prediction and analysis of a regulatory SNP map of Major Depression Disorder.
MEDICAL RESEARCH COUNCIL
May 2008 - April 2011
Four Year PhD Programme in Cellular and Molecular Physiology.
WELLCOME TRUST (UK)
October 2001 - September 2005
Expression and function of the tachykinins in epilepsy.
WELLCOME TRUST (UK)
October 2002 - September 2006
Establishment of a novel technology: Proximity Ligation
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL
September 2007
The mechanisms by which polymorphic domains in the 5HTT gene, potenially correlated with behavioural disorders, modulate gene expression.
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL
June 2006 - May 2009
Molecular analysis of the role of the tachykinins in pain, reward and anxiety.
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL
January 2002 - January 2006
Prediction and analysis of genetic variation which would affect expression of candidate genes associated with Motor Neurone Disease
MOTOR NEURONE DISEASE ASSOCIATION
September 2009 - May 2011
A sensor system to assess the regulation of latency and associated post-herpetic neuralgia in varicella zoster virus
PAIN RELIEF FOUNDATION (UK)
September 2011 - November 2011
11th Multidisciplinary International Conference of Neuroscience and Biological Psychiatry "Stress and Behaviour"? 1st International Stress and Behaviour Society.
ROYAL SOCIETY (CHARITABLE)
May 2008
Four-year PhD programme in cellular and molecular physiology.
WELLCOME TRUST (UK)
October 2004 - September 2008
Prenatal and infancy origins of biological and social-cognitive processes in disruptive behaviour problems in children aged 7 - 9 years.
MEDICAL RESEARCH COUNCIL
August 2014 - January 2020
The expression and function of the neuropeptides substance P and neurokinin-A in nociceptive pathways.
WELLCOME TRUST (UK)
September 2001 - August 2002
Can the genotype of the human serotonin transporter (SLC6A4) generate differential epigenetic signatures over the gene response to exposure to cocaine?
WELLCOME TRUST (UK)
October 2010 - September 2014