Biochemistry

*BBSRC EASTBIO Programme* Immunometabolic targets for healthy ageing

Control of immunity through changes in metabolism-‘immunometabolism,’ if it can be better understood, is recognised as a potential site of intervention to promote healthy ageing (O'Neill et al., 2016); however, existing nonsteroidal anti-inflammatory drugs (NSAIDs) and anti-TNF drugs have shown limited utility in delaying onset of age-related disease.

Palmitoylation and the regulation of the “funny” current HCN4 channel

Applications are invited for a PhD studentship in the laboratories of Dr Will Fuller (Division of Molecular & Clinical Medicine, University of Dundee) and Professor Jules Hancox (School of Physiology and Pharmacology and Neuroscience, University of Bristol). The project will characterise a novel regulatory mechanism of the ion channel ‘HCN4’, which controls the rate of the heart’s intrinsic pacemaker. The project will therefore provide new insights into a hitherto overlooked mechanism by which cardiac pacemaker activity could be modulated.

Personalised medicine for blood pressure and diabetes control and prevention of kidney disease.

The main reason for kidneys to fail is due to diabetes and prolonged exposure to high blood pressure.  These two factors account for nearly three quarters of all kidney disease.   The effectiveness of drugs in the management of blood pressure and diabetes is highly variable in different individuals and it would be desirable to be able to use simple tests to predict which drugs will work in particular patients.   The current project aims to define predictive markers to allow for the more effective prevention of kidney disease in patients with high blood pressure and diabetes.  The student wi

Personalised Medicine in Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is now regarded as the most common liver condition in the developed world, affecting up 30% of the general population. It is closely linked with the metabolic syndrome and its component parts including obesity, type 2 diabetes mellitus (T2DM) and dyslipidaemia, with insulin resistance and excess oxidative stress being the common uniting pathological mechanisms.

Probing the function of individual Cyclin/Cdk complexes during the cell cycle

Background: Cyclin subunits, in combination with their Cyclin-dependent kinase (Cdk) domains, regulate many aspects of cell cycle progression, including DNA replication (Cyclin A2) and cell division (Cyclin B1). Cyclin A2 and Cyclin B1 share the same catalytic subunits, Cdk1 and Cdk2, therefore it is difficult to separate their functions because Cdk1 or Cdk2 inhibitors affect multiple Cyclin/Cdk complexes at once. For example, Cyclin B/Cdk1 is known to stimulate mitotic entry but Cyclin A2/Cdk1 could well play an important undiscovered role.

The regulation of oncogenic signalling through the Ras/MAP kinase pathway by dual-specificity protein phosphatases

Signalling through the classical Ras/ERK MAP kinase pathway is implicated in the genesis and progression of human tumours carrying activating mutations is upstream pathway effectors such as receptor tyrosine kinases and the Ras family of cellular proto-oncogenes.

Spatial feedback controls during mitosis

Background: Two principle surveillance mechanisms have evolved to guard against errors during chromosome segregation. The mitotic checkpoint delays mitosis until each and every sister chromatid has achieved stable attachment to spindle microtubules (via a protein complex known as the kinetochore), and the microtubule error-correction pathway guides this attachment process by ensuring it remains free of errors. In spite of these safeguards, the majority of tumours still manage to continually missegregate their genome.

Control of the cell response to chemotherapy by modulating degradation of p53 protein isoforms

We demonstrated that the p53 tumour suppressor gene expresses at least twelve different p53 proteins due to alternative splicing, alternative initiation of translation and alternative promoter usage. We determined that p53 isoform proteins are expressed in normal human tissue in a tissue dependent manner. P53 isoforms are abnormally expressed in a wide range of cancer and are associated with breast cancer prognosis.

What regulates the alternative splicing of the TP53 gene and how can we take control of it to change cell fate outcome in response to cellular stress?

We demonstrated that the p53 tumour suppressor gene expresses at least twelve different p53 proteins due to alternative splicing, alternative initiation of translation and alternative promoter usage. We determined that p53 isoform proteins are expressed in normal human tissue in a tissue dependent manner. P53 isoforms are abnormally expressed in a wide range of cancer and are associated with breast cancer prognosis.

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