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	Andrea OLSCHEWSKI, MD, PhD The chloride channel regulator CLCA1 and the calcium-activated chloride channel TMEM16A in lung fibrosis
Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz; Auenbruggerplatzt 5, 8036 Graz phone: +43-316-385 72057, fax: +43-316-385 14663, ✉ e-mail
websites: [RESPImmun]
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Andrea Olschewski is an anesthesiologist and electrophysiologist with interest in the regulation of the pulmonary circulation. With her expertise in biophysics, molecular physiology of ion channels she has done pioneering work characterizing the role of ion channels in the human pulmonary vasculature. She has also explored the role of chemokines in vascular smooth muscle function in PH. Within RESPImmun she closely collaborates with Ákos Heinemman (inflammation), Leigh Marsh (animal models), Grażyna Kwapiszewska (molecular biology), Gerald Höfler (lung pathology), Horst Olschewski (clinical samples).

Project

Project 9: The chloride channel regulator CLCA1 and the calcium-activated chlorid channel TMEM16A in lung fibrosis
Co-PI: Chandran Nagaraj

Background

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease. The majority of patients have median survival of 3 – 5 years. IPF is a complex disease, with inflammatory, environmental and genetic factors variably contributing to disease susceptibility and outcomes. Mediators released from inflammatory cells associated with chronic lung diseases such as lung fibrosis are known to elevate intracellular calcium (Ca²⁺) in target cells or directly regulate ion channels. The TMEM family, particularly TMEM16A, is a critical component of Ca²⁺-activated chloride (Cl⁻) channels in various physiological functions and they are widely expressed in lung epithelium. Several key signaling factors affect anion channel activity in inflammatory epithelia: a chloride channel regulator (CLCA1) and TMEM16A. In addition, they support both cell proliferation and regulated cell death. Our recent data provide evidence that CLCA1/TMEM16A expression and function is dysregulated in other chronic lung diseases such as idiopathic pulmonary hypertension (IPAH). However, the relationship between CLCA1, TMEM16A and signalling related to inflammatory mediators is still under investigation. In addition, the possible role of CLCA1 and TMEM16A in pulmonary fibrosis has not been elucidated yet.

Hypothesis and objectives

We hypothesize that the CLCA1 / TMEM16A axis is a novel player in idiopathic pulmonary fibrosis. We will futher characterize the CLCA1 / TMEM16A expression and function in healthy and IPF human lungs and their manipulation by inflammatory modulators leading to parenchymal remodeling and thus to pulmonary fibrosis. Proof-of-concept studies will be performed in mouse models of pulmonary fibrosis.

Methodology

In this project the student will: (i) investigate CLCA1 level in the bronchoalveolar lavage fluid (BALF) and lung homogenate samples from the explanted IPF lungs; (ii) investigate the role of TMEM16A on epithelial cells and its upstream and downstream signaling in lung fibrosis with special focus on inflammatory markers; (iii) prove the importance of TMEM16A in in vivo models of lung fibrosis. Year 1: The PhD student will learn to isolate primary epithelial cells from explanted human lungs. CLCA1 / TMEM16A expression and localisation will be examined by qPCR and flow cytometry followed by confocal fluorescence microscopy. Circulating plasma CLCA1 levels will be measured by ELISA in human samples and in the animal models of pulmonary fibrosis. Year 2: Functional role of CLCA1 / TMEM16A manipulation of epithelial cells will be investigated by patch-clamping, live cell calcium imaging and its impact on cell proliferation and secreted inflammatory mediators. Year 3 – 4: The student will analyse the CLCA1 / TMEM16A axis in well-established experimental mouse models for pulmonary fibrosis (bleomycin-induced fibrosis model and Fra2 overexpressing mice). He / she will perform in vivo measurements such as lung function and morphological analysis. The in vivo findings will be futher validated on human tissue samples.

Input from collaborations within the RESPImmun programme

Ákos Heinemann and Herbert Strobl will support the project with inflammatory cells isolation,
Grażyna Kwapiszewska with the effect of mediators on extracellular matrix,
Horst Olschewski will provide blood and plasma samples,
Leigh Marsh will train the student in experimental mouse models of pulmonary fibrosis and provide expertise in the characterization of inflammatory cells,
Gerald Höfler will support with his expertise on lung pathology.