Mechanisms underlying the development of pulmonary arterial hypertension

Severe pulmonary arterial hypertension (PAH) is a rare but devastating condition with greatly reduced life expectancy. The disease is defined as high blood pressure confined to the lungs. Existing treatments improve symptoms for a time but the majority of patients eventually deteriorate and require escalation of therapy or lung transplantation. Many will eventually die from heart failure. We would be better placed to find curative treatments for this condition if we had a deeper understanding of the underlying causes. We have already learned much from genetic discoveries in this disease. Approximately 25% of patients with severe PAH carry defects (mutations) in a gene called BMPR2. The BMPR2 gene codes for a protein that is normally found on the surface of cells that line the inner walls of blood vessels. This protein sends signals to the inside of the cell to prevent it leaking and dying. When BMPR2 is mutated, the cells lining the blood vessels behave abnormally which leads to severe narrowing of the lung arteries. Currently available treatments do not affect this underlying problem and so have little if any effect on the disease process. This project will address major research questions in this field with the aim of providing a greater understanding of disease mechanisms and new clues as to how we can best treat this condition. We now intend to employ the power of modern genetic techniques to find further mutations in patients with PAH in whom we have excluded mutations in BMPR2. Over the last ten years since the discovery of mutations in BMPR2 we have found promising leads in terms of treatment, but these are not straightforward. The prediction is that looking closely for further mutations will provide us with additional targets that might be easier to transform into new treatments. We know that in the families of patients with BMPR2 mutations, there are many individuals with mutations who have not yet developed the disease. This group is at major risk of developing PAH but the environmental factors responsible for triggering the disease remain unknown. We plan to follow up subjects with BMPR2 mutations but who do not yet have the disease over the next 5 years. At 6 monthly follow up subjects will give blood samples, be assessed clinically for signs of disease and will compete a questionnaire designed to detect environmental exposures. This part of the study will provide important information on risk to individuals with certain mutations and provide new information on potential triggers for disease that can then be avoided or used to design new approaches to treatment. As part of this study we will also prepare to capitalise on information learned from the genetic and environmental information. To do this we will generate patient-specific stem cells from a blood test from individuals with BMPR2 mutations (with and without disease) and from patients in whom we find new mutations. We will begin to use these cells to understand how mutations cause changes in important cell types in this disease, including heart and blood vessel cells, and use this as a means of screening new drugs. Finally we will begin to use patient derived samples (stem cells and blood vessel cells) to test our best ideas so far, based on what we have learned from the available genetic information to date. This definitive national study has the potential to provide major new insights into our understanding of the genetic and environmental causes of PAH and has potential to provide promising new approaches to disease prevention or treatment based on these findings.