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Collaborative Research Center 1213 - Pulmonary Hypertension and Cor Pulmonale

Heart and lung diseases are the leading causes of death and represent the highest socio-economic burden of all diseases worldwide. Pulmonary hypertension (PH) is a progressive disease of multifactorial etiology with poor prognosis, which affects up to 100 million people worldwide in its various subtypes. It is characterized by pathological inward remodeling and loss of patency of the lung vasculature. Challenged with increased afterload, the right ventricle (RV) initially responds to PH with a beneficial “adaptive” hypertrophy, which is, however, often rapidly followed by “maladaptive” changes leading to right heart decompensation and failure, the ultimate cause of death in PH (cor pulmonale).

The program of this Collaborative Research Center (CRC1213) combines basic science approaches and bedside clinical research in a highly interactive network with the aim to elucidate the pathogenic sequelae underlying PH and cor pulmonale and to evaluate novel treatment concepts. We are pursuing an integrated concept in order to understand the common pathophysiological processes and molecular mechanisms that underlie structural pulmonary vascular abnormalities as well as RV adaptation and maladaptation in PH. Prevention of the progression from RV adaptation to maladaptation may open new ways to prevent death from PH.

Our long-term aim is to reverse the remodeling events that lead to PH in order to regain physiological lung vascular structure and function and to develop RV-focused treatment concepts currently not available. The proposal has a strong translational orientation: its projects span the entire spectrum from genetic/epigenetic signatures, molecular pathway mapping, cell and developmental biology, preclinical disease models, and in vivo molecular imaging, to clinical trials, patient registries and cohorts as well as extensive biobanking.

In the first funding period, the most notable findings include the identification of new targets for treatment of experimental PH (cyclin-dependent kinases, RASSF1a), novel mechanisms of oxygen sensing (mitochondrial O2 sensing via cytochrome c oxidase Cox4i2) and new biomarkers (CILP for RV function). In addition, new methods were developed and refined (e.g. pressure volume loops in patients and micro-computed tomography in experimental models). Based on these results, two new projects will enrich the CRC1213´s portfolio: 1) on lung cancer-associated PH, a new form of PH first described by us, and 2) on PH in diastolic dysfunction of the left ventricle. In addition to existing structural measures, the CRC 1213 will continue to support career development of young basic and clinician scientists, as well as equal opportunities and diversity.