In this project, the PhD student will investigate the role of TRPC6 channels in eosinophilic airway inflammation, with a particular focus on allergic asthma. Functional and molecular analyses in human eosinophils and murine models will be combined to elucidate TRPC6-dependent signaling pathways and their contribution to disease pathogenesis. The therapeutic potential of targeting TRPC6 will be evaluated using pharmacological modulators and a house dust mite-induced model of allergic lung inflammation, aiming to identify novel strategies for immune modulation in asthma.
Project Details
Background:
Transient Receptor Potential Canonical (TRPC) channels (TRPC1-7), are nonselective Ca2+ permeable cation channels. While primarily studied in cardiovascular and nervous systems, increasing evidence suggests that these channels are important modulators of homeostatic and pathological immune responses. Among TRPC channels, TRPC6 particularly is highly expressed in human and mouse lungs and plays an important role in airway inflammation1. Our recent data show that TRPC3/6- signaling pathways can be activated in immune cells using TRPC3/6-specific pharmacological tools2 and that TRPC6 is highly expressed in human eosinophils.
Hypothesis and Objectives:
We hypothesize that TRPC6 channels have (patho)physiological roles in eosinophilic airway inflammation. In this project, we will investigate the role of TRPC6 channels in peripheral blood leukocytes from allergic and non-allergic asthmatics as compared to healthy controls. We will further evaluate the value of the TRPC6 channel as a therapeutic target in an in vivo mouse model of house dust mite-induced allergic lung inflammation.
Methodology:
Responses of eosinophils to TRPC6-specific modulators will be investigated using functional assays, including Ca²⁺ influx, chemotaxis, shape change, and apoptosis. The cellular expression of TRPC6 will be analyzed in human and murine lung tissue using in situ hybridization and immunofluorescence. In a translational approach, a well-established house dust mite–induced mouse model3 will be used to assess the role of TRPC6 in disease pathogenesis through lung function testing and flow-cytometric immunophenotyping of lung tissue and bronchoalveolar lavage fluid (BALF). Cytokines and lipid mediators in serum, lung tissue, and BALF will be quantified by ELISA and mass spectrometry. In parallel, TRPC6 expression and functional activity will be compared in eosinophils from asthmatic patients and healthy controls. Finally, the cellular localization of TRPC6 and its downstream signaling pathways will be examined using Ca²⁺ imaging and immunofluorescence, employing novel TRPC3/6 photopharmacological inhibitors in murine bone marrow–derived and human eosinophils.
References
1. R. L. Corteling et al., Am J Resp Cell Mol 30, 145-154 (2004)
2. B. Bacsa et al., Front Immun 11, 613194 (2020)
3. Teppan et al., Front Immun 15, 1408772 (2024)
People Involved
Primary supervisor: Bernadett Bacsa