Medicine

Linking Genomics to Imaging data: Elucidation of the mechanisms of novel genes that predispose to heart disease

Genome wide studies have provided great insight into the truly polygenic nature of cardiovascular disease, with current meta-analysis being performed in populations of ~200,000 study individuals.  This has characterised around 60 loci involved in susceptibility to CAD.  This analysis combines a wide range of cardiovascular phenotypes including angina, IMT, atheroplasty and MI. So the role of these genes in individual components of cardiovascular disease such as atherosclerosis, vessel damage, heart muscle physiology etc. has not yet been elucidated.

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.

Leptin: a novel therapeutic target in Alzheimer’s disease?

Alzheimer’s disease (AD) is a progressive brain disorder that leads to profound cognitive and memory impairments. The prevalence of AD is predicted to rise rapidly in the future, which will pose a huge burden on health care services in the coming years. Evidence is growing that diet and lifestyle are key risk factors for developing AD and clinical studies indicate that metabolic dysfunction is a common trait in AD.

Environmental stress and the brain

The last few decades has seen a marked increase in the incidence of both type 1 and type 2 diabetes in Western Societies resulting in a significant individual and societal health costs. Understanding those mechanisms that contribute to the development of obesity and disorders of glucose homeostasis are therefore critical areas of research. It is increasingly recognized that the brain contributes to the development of both diabetes and obesity.

Regulation of the Sodium Pump By Palmitoylation of its Accessory Subunits

The plasmalemmal sodium pump is the principal consumer of ATP in the body. In cardiac muscle, the pump is essential for normal cardiac function. In skeletal muscle, the sodium pump controls extracellular potassium concentration and therefore membrane potential and muscle fatigue. In the kidney, the ion gradients established by the pump are critical for reabsorption of water and solutes throughout the nephron, and therefore in the control of blood volume, blood pressure and cardiac load.

The spatio-temporal dynamics of induction of the Keap1/Nrf2 pathway

Multicellular organisms are equipped with elaborate networks of cytoprotective proteins (e.g., glutathione transferases, NAD(P)H: quinone oxidoreductase 1, heme oxygenase 1) that defend against the damaging effects of oxidants and electrophiles, the principal contributors to the pathogenesis of chronic diseases. Under basal conditions, these genes whose transcription is dependent on transcription factor Nrf2, are not expressed at their maximum capacity, but can be upregulated (induced) by a variety of synthetic and natural agents (inducers).

Determining how BACE1 activity regulates neuronal glucose metabolism

A high proportion of the UK population is obese and this is associated with significantly increased risk of type 2 diabetes (T2D), cardiovascular disease and Alzheimer’s disease (AD).  AD is also associated with increased risk of T2D and AD patients and AD animal models demonstrate disturbances in glucose metabolism. The aspartic protease BACE1 (beta-site amyloid precursor protein (APP)-cleaving enzyme) is thought to be the primary driver for the neurodegeneration and cognitive dysfunction associated with AD.

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