Benzodiazepines discontinuation in an animal model

The benzodiazepines were developed as effective anxiolytics; these agents are still commonly used today. The benzodiazepines work quickly and are well tolerated. Their primary disadvantages are sedation, ataxia, impaired memory, and cognition and, after chronic administration, physiological dependence and withdrawal symptoms upon discontinuation. A withdrawal syndrome, characterised by increased anxiety related behavioural responses, is established in animals following two weeks treatment and abrupt withdrawal. This model can facilitate the study of the mechanism underlying the syndrome as well as exploration of novel treatment approaches. We have established that behavioural concomitants of the syndrome can be alleviated by acute treatment with the non-specific serotonin antagonists. The current study seeks to expand on this observation by examining the ability of more specific serotonin antagonists to alleviate withdrawal induced behaviours in the rat.

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Biochemical and functional analysis of the gamma-secretase subunit APH-1

This project will investigate the expression and characterization of APH-1, a subunit of the gamma-secretase complex that is implicated in Abeta amyloid production and in the pathogenesis of Alzheimer’s disease. This involves the use of biochemistry, cell culture, and molecular biology techniques.

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Biochemical and Physiological Characterisation of IRAP

Co-Supervisors: Dr Anthony Albiston, Dr Vi Pham, Dr Shanti Diwakarla

Metallo-peptidases cleave amino acids from either the N- and C-termini of peptide substrates to either generate or degrade biologically active peptides and the activity and their activities are dependent on the presence of zinc in the catalytic sites. These enzymes play important roles in the body and alterations in their activities can impact on a diverse range of physiological processes in both healthy and diseased states. Research in the Neurochemistry team has focussed on the metallopeptidases involved in the processing of angiotensin peptides. Our findings have revealed previously unsuspected and more widespread roles for these enzymes, particularly their involvement in memory processing, glucose homeostasis, cardiovascular function and water and electrolyte balance. We have a drug development program targeting one of these enzymes (IRAP) and have identified two families of lead compounds that await development into a new class of clinically effective cognitive enhancers useful in treating dementia.

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Biochemical and proteomic analysis of the gamma-secretase complex

Alzheimer’s disease Aß amyloid peptide is produced from a large precursor, by two sequential proteolytic cleavages due to beta-secretase and gamma-secretase.

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Bioengineering astrocytes to rescue neurones

Co-supervisors: Dr Clare Parish, Dr Linda Lau & Prof Malcolm Horne

This project aims to optimise regeneration in injured brain by growing astrocytes in a pro-survival phenotype on nanofibrous scaffolds suitable for transplantation to aid re-establishment of host circuitry.

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