Immune / vascular endothelial cell crosstalk drives pathogenic remodelling
Grazyna Kwapiszewska-Marsh, Otto Loewi Research Center (Physiology), Medical University of Graz/ Ludwig Boltzmann Insititute for Lung Vascular Research
PD Dr. Grazyna Kwapiszewska-Marsh|
|Availability:||This position is available.|
Medical University of Graz
|Application deadline:||Applications are accepted between August 14, 2020 00:00 and October 10, 2020 23:59 (Europe/Zurich)|
Vascular abnormalities are a common feature of chronic lung diseases, such as pulmonary fibrosis (PF). These abnormalities manifest as pulmonary arterial remodelling and obliteration, as observed in pulmonary hypertension (PH), or as changes in vascularity and vessel distributions as observed in PF. Current studies indicate that endothelial cell (EC) dysfunction, with increased endothelial cell apoptosis and hyperproliferation of remaining apoptosis-resistant cells are key pathomechanisms underlying vascular remodelling. Moreover, immune cells can actively modulate EC behaviour and fostering disease progression. We have previously shown pronounced pulmonary vascular remodelling in PF, and that the immune cell signature is strongly altered and associates with vascular remodelling (Hoffmann, 2014; Marsh, 2018). Further we shown that transcription factor fos-realted antigen-2 (Fra-2) is a master regulator of pulmonary vascular and parenchymal remodelling, and controls the immune response (Birnhuber, 2019a, b).
Hypothesis and Objectives:
We hypothesize that altered cross-talk between immune and EC leads to vasculopathy and consequently to development of pulmonary fibrosis. Using a wide array of methods and models, we will investigate the influence of Fra-2 on EC function and EC crosstalk with immune cells in the development of pulmonary fibrosis.
Characterisation and isolation of immune cells will be conducted by flow cytometry, cell-sorting and MACS approaches. Disecting of the immune and EC cross-talk will be achieved in co-culture systems. The receptor–ligand interaction will be analysed in silico as well as in vitro. Primary endothelial cell cultures from healthy and diseased lung tissue (human and murine) will be performed for in vitro assays to assess endothelial cell function. Studies on human lung tissue will complement the variety of in vivo approaches. Additionally, in vivo approaches in the lineage tracing mouse models (El Agha, 2017; Crnkovic 2018) will prove validity of our findings.
- Hoffmann J, Wilhelm J, Marsh LM, Ghanim B, Klepetko W, Kovacs G, Olschewski H, Olschewski A, Kwapiszewska G. Distinct differences in gene expression patterns in pulmonary arteries of patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis with pulmonary hypertension. Am J Respir Crit Care Med. 2014 Jul 1;190(1):98-111.
- Marsh LM, Jandl K, Grünig G, Foris V, Bashir M, Ghanim B, Klepetko W, Olschewski H, Olschewski A, Kwapiszewska G. The inflammatory cell landscape in the lungs of patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2018 Jan 25;51(1):1701214. doi: 10.1183/13993003.01214-2017
- Birnhuber A, Crnkovic S, Biasin V, Marsh LM, Odler B, Sahu-Osen A, Stacher-Priehse E, Brcic L, Schneider F, Cikes N, Ghanim B, Klepetko W, Graninger W, Allanore Y, Eferl R, Olschewski A, Olschewski H, Kwapiszewska G. IL-1 receptor blockade skews inflammation towards Th2 in a mouse model of systemic sclerosis. Eur Respir J. 2019 Sep 29;54(3). pii: 1900154.
- Birnhuber A, Biasin V, Schnoegl D, Marsh LM, Kwapiszewska G. Transcription factor Fra-2 and its emerging role in matrix deposition, proliferation and inflammation in chronic lung diseases. Cell Signal. 2019 Dec;64:109408.
- El Agha E, Moiseenko A, Kheirollahi V, De Langhe S, Crnkovic S, Kwapiszewska G, Szibor M, Kosanovic D, Schwind F, Schermuly RT, Henneke I, MacKenzie B, Quantius J, Herold S, Ntokou A, Ahlbrecht K, Braun T, Morty RE, Günther A, Seeger W, Bellusci S. Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis. Cell Stem Cell. 2017 Apr 6;20(4):571. doi: 10.1016/j.stem.2017.03.011.
- Crnkovic S, Marsh LM, El Agha E, Voswinckel R, Ghanim B, Klepetko W, Stacher-Priehse E, Olschewski H, Bloch W, Bellusci S, Olschewski A, Kwapiszewska G. Resident cell lineages are preserved in pulmonary vascular remodeling. J Pathol. 2018 Apr;244(4):485-498.