Respiratory diseases range from the mild and self-limiting such as the common cold, to life-threatening. This latter group includes diseases such as severe infections, blood clots, cystic fibrosis, chronic obstructive airways disease, and lung cancer. In particular, malignant tumours of the respiratory system are responsible for 15% of all cancer diagnoses and 30% of all cancer deaths. Our division is working to improve the outcomes for these patients by revealing some of the early events that are critical to the development of squamous lung cancer (SQC). By using preclinical model systems we deconstruct the functional impact of pathogenesis and define therapeutic vulnerabilities, using this information to develop approaches for early detection and prevention.
Other respiratory diseases are the product of internal stresses within the cells of the respiratory system. They can be caused by proteins that are destined for insertion into the cell membrane or secretion outside the cell. This process relies upon proteins being correctly folded, but can become defective in disease states such as hypoxia, malignancy and some forms of diabetes. This causes increased levels of these proteins and affects tissue growth and cell survival. We therefore identify the genes required to regulate the degradation of proteins by genetic screening. These cellular processes are also regulated by the local oxygen and nutrient environment. Central to this are the hypoxia inducible transcription factors (HIFs), which are usually degraded when oxygen is abundant. However, we find that HIFs can be stabilised and activated even in aerobic conditions, which has uncovered a novel regulatory pathway for oxygen sensing and continues to drive our search for the regulatory genes responsible.
Immune responses are also affected by disease and our work with radiolabelled immune cells allows us to examine the fates of these cells using body scanning techniques in patients. This is important as immune cells that have previously been exposed to stimuli will react to a second stimulus with an increased response. This is a critical determinant of their pathogenic capacity, and our work has helped scientists understand the process of immunity within the lungs. These organs can also be affected by high blood pressure resulting from pulmonary arterial hypertension (PAH). We lead large national and international studies to identify novel genetic drivers of PAH, as well as drivers of chronic thromboembolic pulmonary hypertension, a disorder associated with significant mortality. Our research reveals the causes of dysfunctional signalling, gene transcription and vascular cell biology. It also suggests new approaches to rescue these deficiencies by gene therapy and by inhibiting the turnover of cellular components using existing drugs. This research has led to a university spin-out company, MORPHOGEN-IX to take these innovations to the clinic.