*4 Year MRC PhD Programme* Role of the HIF-NF-kappaB crosstalk in cardiovascular disease

Chronic Heart Failure is characterised by the presence of chronic hypoxia and inflammation, both of which are intertwined at molecular, cellular, and clinical levels [1]. Cellular adaptations to hypoxia rely on the transcription factor Hypoxia Inducible Factor (HIF), which is inactive when oxygen is abundant through the action of prolyl-4-hydroxylase domain enzymes (PHD) but is activated in hypoxic conditions. Members of the nuclear factor kB (NF-kB) family of transcription factors regulate inflammation and orchestrate immune responses and tissue homeostasis. It is known that members of this NF-kB family interact with members of the PHD-HIF pathway in ways that link inflammation to hypoxia [1-4] but the role of each subunit and the interplay between them, particularly in hypoxia related to cardiovascular disease, is unclear and therefore mechanistic research will address these questions. This project will investigate the relationship between HIF and NF-kB in the context of cardiovascular disease by combining the mechanistic studies in the Rocha lab, with the clinical knowledge and samples from the George lab. Analysis of HIF levels and NF-kB activity levels will be performed in vitro, using cardiomyocytes and endothelial cells exposed to hypoxia (acute and chronic) as well as inflammation, and in the blood of normal healthy donors and patients with different types of cardiovascular disease. In in vitro models, genetic manipulation as well as chemical perturbation of the pathways will be performed. Research laboratory training in state of the art techniques, including quantitative imaging and quantitative molecular approaches and also clinical practice and research training will be provided under this joint project.