Morty Lab | Voswinckel/Seeger Lab | Pullamsetti Lab | AG Savai

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Department I

Cardiac Development and Remodelling
Prof. Dr. Dr. Thomas Braun

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Pharmacology
Prof. Dr. Stefan Offermanns

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Developmental Genetics
Dr. Didier Stainier

Department IV

Lung Development and Remodelling
Prof. Dr. Werner Seeger

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Molecular Mechanisms of Pulmonary Vascular Diseases

Lab Leader:

Dr. Soni Savai Pullamsetti

Pulmonary hypertension (PH) is a progressive disease of multifactorial etiology, which has a poor prognosis and results in right heart failure. Based on histopathological appearance and treatment modalities, five subclasses of chronic pulmonary hypertension have been defined. However, to date, current PH therapy provides symptomatic relief and improves prognosis, but falls short of re-establishing structural and functional lung vascular integrity, and thus, handicap-free long-term survival.

Molecular dissection of pathogenic pathways of different forms of PH, and the development of therapeutic strategies to reverse structural abnormalities of the lung vasculature and cardiac remodeling in this devastating disease represent the major research focus of this work group.

Idiopathic pulmonary fibrosis (IPF) belongs to the family of idiopathic interstitial pneumonias (IIPs), representing the most aggressive form of a diffuse parenchymal lung disease (DLPD) and affecting up to 500 000 patients in the western world. With the exception of pirfenidone, there are currently no approved therapies for IPF, and IPF is still a disease with significant morbidity and mortality.

Unraveling the molecular basis behind the remodeling events in the lung parenchyma, resulting in the loss of gas exchange units and the deposition of scar tissue in lung fibrosis, is desirable. This work group will focus on two of signaling cascades: Forkhead box O (FoxO) transcription factors and histone acetylation/deacetylation, and their contribution to the pathogenesis of IPF.

Transcription factors

Increased proliferation, migration and anti-apoptosis of pulmonary vascular cells play a major role in pathologic inward remodeling processes underlying different variants of pulmonary hypertension (PH). Transcription factors can induce profound and sustained phenotypic effects in cells by binding and altering the expression of thousands of genes. It is therefore postulated that many of these factors have been shown to play critical roles in lung diseases, especially in PH.

Forkhead box 0 (Fox0) transcription factors are key regulators of cellular proliferation, migration, differentiation, apoptosis and ageing by modulating and integrating multiple signaling pathways (P13K/Akt, MAPK, NFkB, SMAD, ß-catenin). We aimed to determine the changes in the expression and function of Fox0s in response to different stimuli relevant to the development of PH and to determine the impact of Fox0 expression/function on pulmonary artery remodeling or reverse remodeling during the developmnet of PH in vivo.

To elucidate the complex role of GSK-3 and ß-catenin (transcriptional co-activator which is negatively regulated by GSK-3) during pulmonary vascular and cardiac-remodeling.

Epigenetic mechanisms

The contribution of epigenetic mechanisms to PH remains poorly understood. Epigenetic modifications of histone tails include acetylation, methylation, ubiquitination and SUMOylation of lysine residues, phosphorylation of serine residues and methylation of arginines. We postulate that epigenetic changes may contribute to the pathogenesis of vascular lesions and modify properties and gene expression in lesion cells and might hold therapeutic promise in PH.

To characterize the histone modifications in remodeled pulmonary vasculature and to delineate the role of histone acetylation by the enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs).
To characterize histone methylation changes in remodeled pulmonary vasculature.