Treating diabetic inflammation using AMP-activated protein kinase activators: Working with industry. Medical Studies, PhD (GW4 BioMed MRC DTP)

Supervisory team:
Dr Craig Beall, University of Exeter Medical School
Dr Kate Ellacott, University of Exeter Medical School
Dr Malcom Watson, University of Bath

Inflammation is common in diabetes and contributes to disease by increasing risk for heart attacks and strokes. In this project, the student will use novel drugs targeting the AMP-activated protein kinase (AMPK) pathway. We will work with Rigel Pharmaceuticals, Inc., to determine whether drugs targeting AMPK reduce inflammation caused by diabetes.

Too much and too little sugar is bad for you. For example, people with type 2 diabetes experience chronically elevated blood sugar levels, which is associated with chronic low grade inflammation. This contributes to disease progression and the development of diabetic complications such as heart disease and nerve damage. Interestingly, bouts of glucose insufficiency (known as hypoglycaemia) also cause inflammation. This “yo-yoing” occurs frequently in diabetes and raises the interesting concept: how does too much and too little energy cause inflammation?

Central to our hypothesis is that an energy sensing enzyme, AMP-activated protein kinase or AMPK for short, will play a role. This enzyme is activated when energy supply is limited and suppressed when energy levels are high. Therefore, activation of AMPK using drugs gives a signal of starvation, even without an energy deficit. This pseudo-starvation state gives rise to anti-inflammatory signalling. Supporting this, the most widely used anti-diabetic medication, metformin, is anti-inflammatory, at least in part by activating AMPK. To test the hypothesis that AMPK directly/indirectly regulates whole body inflammation in diabetes, we will use novel pre-clinical AMPK-activating drugs. We are collaborating with Rigel Pharmaceuticals Inc. (San Francisco, CA, USA), testing their pre-clinical 2nd generation metformin-like drugs

We will perform comprehensive in vivo metabolic phenotyping to assess glucose handling, including in vivo glucose clamping. We will examine the consequences of our interventions on changes in body weight, food intake and inflammatory markers. Several imaging-based approaches will also be utilised, including fixed tissue analysis using confocal and widefield microscopy as well as live-cell/tissue imaging by 2-photon microscopy and calcium imaging.

Importantly, this studentship will provide the candidate with a secondment period at Rigel Pharmaceuticals, Inc. in San Francisco, USA, where the candidate will gain a valuable insight into the workings of the pharmaceutical industry. Back at home, this studentship will provide excellent training in in vivo methodologies for investigating metabolism and inflammation. The candidate will join a research team with a proven record in research and student development and will become a key member of a vibrant research team in Exeter with 2 postdoctoral researchers, 5 PhD students and 2 research technicians (CB and KE groups). In Bath, MLW has a postdoctoral researcher working on inflammation signalling and other projects in collaborating laboratories are assessing signalling events in a range of inflammatory diseases.

To apply for this project please complete the application form at https://cardiff.onlinesurveys.ac.uk/gw4-biomed-mrc-dtp-student-2019 by 5pm Friday 23 November 2018.