Applications are invited for a British Heart Foundation-funded position of Post-Doctoral Research Associate to investigate the complex process of systemic metabolic adaptation during the initiation and development of pulmonary hypertension (PH). You will join the Hypoxia and Inflammation research group, led by Dr Andrew Cowburn in the National Heart and Lung Institute (NHLI). Dr Cowburn works with a team of basic and clinician scientists challenging our understanding of oxygen sensing in the pathophysiology of inflammation and disease.
The research brings together the major disciplines of metabolomics, hypoxia signalling and cardiopulmonary biology, and follows the seminal discovery by Group Cowburn that HIF2a signalling forms a key component in the development of pulmonary hypertension in pre-clinical models (Cowburn et al, PNAS 2016; Macias et el, ERJ 2021). This is vital to understand critical systemic metabolic reprogramming events associated with pulmonary arterial hypertension (PAH), and how these maladaptive processes in distal tissues contribute to increased patient morbidity and mortality. The combined analysis of metabolic data with tissue-specific respirometry and gene expression profiles will determine whether cardiopulmonary and systemic tissues follow comparable metabolic dysregulation and identify the tissue origin of metabolic dysfunction during PH development. This detailed longitudinal analysis of metabolic homeostasis throughout the progression of PH will help to identify novel biomarkers/pathways related to disease development and thus identify novel therapeutic opportunities targeting metabolic dysfunction; thus the project has significant translational potential.
We will use two pre-clinical models (Sugen5416/hypoxia and monocrotaline) to longitudinally follow metabolic adaptation process from the point of disease initiation through to end-stage right ventricle maladaptation. We will use a drug intervention strategy to question the role of HIFa signalling in these metabolic processes. We will determine PAH disease severity by cardiac ultrasound using the Fuji-sonics vevo3100 before analysis of whole-body metabolism using the Columbus instruments CLAMS and collection of breath samples to determine exhaled metabolites. We will collect multiple tissues at set time points throughout the PH disease cycle to identify organ specific metabolic adaptation using high resolution respirometry, RNA-seq, histology and lipidomics. These model systems combined with whole-body and breath metabolic profiles from PAH patients will allow us to validate patient metabolic status and disease severity.
These methodologies are eminently clinically translatable as non-invasive procedures to monitor: i) disease progression, ii) metabolic target engagement during clinical intervention studies or iii) response to established treatments in PAH patients.
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