Investigating the role of redox signalling regulating anti-angiogenic factors in cardiovascular disease using organ-on-a chip and in vivo models

Oxidative stress is explicitly linked with cardiovascular disease.  Oxidative post-translational modifications (oxPTM) of receptors, enzymes and transcription factors play an important role in cell signalling. oxPTMs are a key-way in which oxidative stress can influence cell behaviour during diverse pathological settings such as cardiovascular diseases (CVD). In addition, changes in oxPTM are likely to be ways in which low level reactive oxygen and nitrogen species (RONS) may contribute to redox signalling, exerting changes in physiological responses including angiogenesis and cardiac remodelling. 

In the disease setting upsetting the redox homeostasis leads to elevation in oxidative stress and endothelial dysfunction.  In obesity and diabetes, endothelial dysfunction often precedes the clinical signs of peripheral artery disease or cardiac hypertrophy.   Understanding the redox sensitive pathways involved in the early stages of disease development is important for targeted therapy.

In this project to decipher the impact of redox signalling on endothelial function we will use a combination of in vivo and in vitro studies. The clinical setting will be mimicked using hind limb ischemia or transverse aortic constriction models.  Cutting-edge in vivo phenotyping (telemetry, laser doppler imaging, left ventricle pressure volume loop) will be applied to novel genetically modified models to understand the physiological role of redox signalling on angiogenesis in peripheral artery disease and cardiac hypertrophy. In addition, this project will utilise stem cell technology to model pathological conditions in combination with this emerging organ-on-a-chip technology to assess redox control of endothelial function via regulation of anti-angiogenic factors.  Advancing these multicellular models will pave the way for high throughput drug screening targeted at endothelial function and the redox pathways. 

This translational project will enable the student to conduct in vivo cardiovascular pre-clinical modelling in combination with in vitro 3D cell technology to interrogate molecular pathways involved in cardiovascular disease.