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Pulmonary Hypertension: Functional Genomics and Therapy of Lung Vascular Remodelling

Final Report Summary - PULMOTENSION (Pulmonary Hypertension: Functional Genomics and Therapy of Lung Vascular Remodelling)

Pulmonary hypertension (PH) describes a group of devastating diseases, comprising hereditary, idiopathic and secondary forms, which cause breathlessness and premature death, representing a major burden on healthcare systems. Extensive lung vascular remodelling with loss of vessel patency is the underlying pathomechanism in PH. PULMOTENSION integrated the top European centres in PH and lung vascular biology in a multidisciplinary approach, with the aim to combat and finally maybe even find a cure for PH. The expertise of all members fully extends from the initial discovery of gene mutations causative of PH to having established new therapeutic regimen of PH. The project has identified and analysed different underlying molecular pathways, identified distinct targets for anti-remodelling therapy, fostered drug development based on these targets, and tested these new treatment options in preclinical and clinical trials.

Deciphering of the functional genomics of lung vascular remodelling and identification of new molecular targets to alleviate or even cure pulmonary hypertension has been the main objective of this project. To this end, the work of the consortium spans the entire field from basic research to clinical studies.

The project has characterised a number of different molecular mechanisms underlying the dramatic remodelling processes in the lung vasculature, which result in an increase in vascular resistance by more than one order of magnitude. To this end, genetics, functional genomics, and proteomics have been combined with cell culture studies, experimental pulmonary hypertension animal models, and analysis of clinical tissue bank material. A survey of PH patients has been conducted covering three major European centres for disease management; diagnostic tools for non-invasive diagnosis of lung vascular and right heart remodelling are being tested. Finally, based on the identification of new genes and signalling pathways as novel therapeutic targets, preclinical and clinical studies with focus on anti-remodelling treatment have been performed and are still underway. In all aspects, gender differences have been particularly addressed. The members of the consortium have jointly managed to carry out an ambitious translational research programme, with the intent to perform an analysis from molecules to patients. According to the scientific nature of our project, generation of new knowledge and improvement of PH patient therapy have been the primary goals of the consortium. Publications in international peer reviewed journals, patents, evaluation of new diagnostic and therapeutic approaches, standardisation of these techniques throughout Europe, and information to society are important measurable objectives in this respect. Due to the strong translational research infrastructure of the consortium, we expect innovative therapies to become available for patients suffering from PH, as a result of the work of this consortium. This has already been implemented in two clinical trials conducted within the frame of this Integrated Project (IP) and will be further followed based on the results gained during the project's lifetime. The objectives also include the promotion of a long-lasting European infrastructure for scientific and technical competence in the field of vascular remodelling and PH. Training and mobility programs, especially for young researchers, mechanisms for technology transfer and educational programs, and are being continued with partners of the consortium.