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• Olschewski H
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The RESPImmun Faculty

	Gunther MARSCHE, PhD Lysophosphatidylcholines and eosinophil function
Otto Loewi Research Centre, Division of Pharmacology, Medical University of Graz, Neue Stiftingtalstraße 6, A-8010 Graz; phone: +43-316-385 74128, fax: +43-316-385 79613, ✉ e-mail
websites: [RESPImmun]
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Gunther Marsche is a biochemist and pharmacologist whose aim is to identify and characterize novel mediators of inflammation, with a focus on lipid mediators derived from hydrolysis of phospholipids. He is currently exploring how lysophospholipids affect eosinophil effector responses and endothelial function; thus, they may serve as novel therapeutic targets for both vascular diseases as well as other inflammatory diseases. Within RESPImmun he collaborates with Andrea Olschewski (inflammatory mediators), Ákos Heinemann, Eva Böhm, Leigh Marsh (animal models), Grażyna Kwapiszewska (transcriptomic analysis), Horst Olschewski (patient samples) and Gerald Höfler (pulmonary pathology).

Project

Project 4: Lysophosphatidylcholines and eosinophil function
Co-PI: Katharina Jandl

Background

With a growing interest in the involvement of extracellular lysophosphatidylcholines (LPCs) in both normal physiology and pathology, it has become evident that LPCs may have therapeutic potential. Recent data from our lab suggest that LPCs can regulate basic cellular activities by modulating several molecular targets, e. g. by binding to specific receptors and/or altering the structure and fluidity of lipid rafts. Eosinophils are key factors in asthma exacerbation and airway eosinophilia is present in 50 to 60 % of asthmatics. Interestingly, both the activity of secretory phospholipases and LPC levels in bronchoalveolar (BAL) and nasal lavage fluid increases significantly in patients with either asthma or allergic rhinitis. As eosinophils express and secrete large amounts of secretory phospholipases of type X and IIA capable of cleaving phospholipids into LPCs and free fatty acids, it is likely that they are the major source of increased LPC levels in asthmatic patients. This is also exposing them to high levels of LPCs, yet the effect of LPCs on eosinophil activation and recruitment in the setting of allergic asthma so far remains elusive.

Hypothesis and objectives

Both serum levels of LPCs and circulating eosinophil numbers are associated with increased severity of asthma, yet so far, the functional role of LPC on eosinophils has remained poorly investigated. Here, we hypothesize that LPCs have an immunomodulatory function on eosinophils in allergic inflammation, thereby presenting a promising therapeutic target. In this project, we aim to investigate the functional role of the major LPC species on effector responses of human primary blood eosinophils and on human eosinophil–endothelial cell interaction. This project will also test the direct therapeutic ability of LPC in in vivo models of eosinophil recruitment and ovalbumin-induced allergic lung inflammation.

Methodology

Year 1: The student will learn how to isolate eosinophils from peripheral blood. Functional responses of eosinophils and endothelial cells will be investigated in assays for shape change, integrin upregulation, chemotaxis, Ca²⁺ signaling and endothelial barrier function (electrical impedance measurements). Year 2 – 3: Further techniques the student will acquire include flow cytometry to determine the expression of receptors and adhesion molecules, eosinophilic endothelial adhesion assays under flow, western blotting to study LPC triggered signaling pathways, multiplex ELISA to measure cytokine release, immunofluorescence microscopy, assays to detect reactive oxygen species, phagocytosis and degranulation. Year 3 – 4: The student will test the effects of LPCs on the chemotaxis of eosinophils in IL-5 Tg mice and learn how to stain lung tissue by immunohistochemistry or in situ hybridization. In addition, the student will investigate effects of LPC in established experimental mouse models for allergic asthma. These mouse models are available in the consortium.

Input from collaborations within the RESPImmun programme

Ákos Heinemann will train the student in isolating eosinophils from the blood,
Grażyna Kwapiszewska will supervise the student when assessing LPC-induced downstream signaling in eosinophils and endothelial cells using transcriptomic analysis,
Eva Böhm and Julia Kargl will train the student in chemotaxis assays of eosinophils in vivo,
Horst Olschewski will provide serum from patients with eosinophilic asthma,
Gerald Höfler will support the student with his expertise on lung pathology,
Andrea Olschewski will support with in vivo cell calcium imaging.