Medicine

Cocaine Addiction and α2-GABAA Receptors

The laboratory is part of an MRC-funded multidisciplinary “addiction cluster”. Understanding the basic neurobiological mechanisms by which drugs of abuse become addictive is essential for the future development of strategies to combat drug addiction. Addictive drugs have in common that they influence the function of the pathways in the brain mediating reward, particularly the nucleus accumbens, a region which consists almost exclusively GABA-ergic neurones. Our collaborators studying cocaine addicts have implicated the α2-GABAA receptor isoform in cocaine abuse.

Mutations in the Garb1 gene promote ethanol consumption: Exploring a genetic and physiological basis for alcoholism.

Alcohol addiction is difficult to study in humans due to genetic and environmental complexities. Two mouse lines have been identified that exhibit a greatly increased voluntary consumption of ethanol and harbour single but distinct nucleotide mutations of the GABAA receptor (GABAAR) β1 subunit gene. Importantly, in the nucleus accumbens, a region associated with reward/addiction, we found GABAAR inhibition to be greatly enhanced in these mice as the mutant receptors now open spontaneously i.e. without the neurotransmitter GABA.

TGF-beta signalling in cancer stem cells and metastasis

TGF-beta can act as both a potent tumour promoter and tumour suppressor in a context dependent fashion. During cancer progression tumour cells can modify their response to TGF-beta from anti-proliferative to pro-tumourigenic whereby they can utilise TGF-beta to promote tumour cell proliferation, survival, motility, invasion, intravasation, extravasation, metastatic colonisation and promotion of cancer stem cell straits.

The RNA helicase p68 (DDX5) as a selective modulator of p53-dependent cell cycle arrest and apoptosis

p68 (DDX5) is a prototypic member of the DEAD box family of RNA helicases that can unwind RNA in a context-selective and ATP-dependent manner. p68 is a multi-functional protein known to be involved in several cellular processes requiring manipulation of RNA structures, including transcription and processing of pre-mRNA, rRNA, and miRNA.

Drug safety and improving primary care prescribing safety

Prescription drugs are high-benefit but also high-risk for patients. However, the harms of treatment are often poorly quantified by the randomised controlled trials that define benefit and these trials often exclude the majority of real-world patients with target conditions because of higher risk of harm. This creates the need for observational research to quantify the risks of drugs in real-world populations (pharmaco-epidemiology). Even for drugs where the risks are well-known, we have shown that high-risk prescribing is common.

Clinical gait analysis of patients with cerebral palsy using musculoskeletal computer modelling techniques

Patients with cerebral palsy (CP) usually have muscle weakness resulting in poor muscle control, which makes walking difficult. Given that any clinical intervention aims to improve muscle control, it is crucial to monitor the changes in the muscles during gait. To date however, there has been no means with which to measure muscle characteristics (e.g. muscle force and work) directly and effectively, especially during walking, due to both technological and ethical reasons.

Analysis of the molecular basis of individuality in RTK pathway expression in human ovarian tumours – identification of patient selection biomarkers for personalised cancer medicine

Growth factors (e.g. EGF, FGF, PDGF, VEGF) and associated receptor tyrosine kinases (RTKs) regulate key signal transduction pathways which are frequently dysregulated in cancer. RTK pathways are common targets in chemotherapy drug development, but optimal patient selection and drug efficacy is often limited by lack of target specificity.

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