This project examines how TRPC1/3/6 ion channels influence calcium dynamics in pulmonary vascular cells, contributing to disease-related remodeling. Integrating photo-pharmacology, advanced imaging, ion-channel physiology, and bioinformatics, we aim to uncover novel strategies to modulate vascular tone. The PhD candidate will train across murine and human systems, bridging basic science and translational medicine.
Project Details
Background:
Pulmonary vascular diseases characterized by progressive vascular remodeling of small pulmonary arteries, lead to elevated pulmonary vascular resistance and right heart failure. Endothelial dysfunction and excessive proliferation of smooth muscle cells, both associated with altered calcium (Ca²⁺) homeostasis are key players in these processes. TRPC channels are critical regulators of intracellular Ca²⁺
levels and are implicated in vascular remodeling¹,². Understanding their role could uncover novel therapeutic targets for selective modulation of pulmonary vascular tone.
Hypothesis and Objectives:
Our preliminary data indicate compartment-specific expression of TRPC1/3/6 channels in pulmonary arteries from healthy donors and patients with severe pulmonary vascular disease. We hypothesize that dysregulated activity of these TRPC channels alters Ca2+ homeostasis, contributing to vascular remodeling and elevated pulmonary vascular tone. To test this, we will: i) investigate TRPC1/3/6 function in pulmonary vascular cells using photoswitchable modulators; ii) assess the impact of TRPC-mediated Ca²⁺ signaling on vasoreactivity and vascular integrity and iii) evaluate light-controlled TRPC modulation as a therapeutic strategy.
Methodology:
This PhD project explores the role of TRPC channels in pulmonary vascular cells using both murine models and human donor lungs. The student will isolate endothelial and smooth muscle cells, and apply genetically encoded calcium indicators to monitor real-time Ca²⁺ dynamics in live cells and intact tissues. To precisely control calcium influx, photoswitchable TRPC modulators will be used in combination with advanced imaging techniques. Precision-cut lung slices (PCLS) will preserve the 3D lung architecture. A range of assays will assess TRPC-mediated effects on vasoreactivity (via small-vessel myography and ex vivo murine lung system), barrier integrity (TEER), cell proliferation, and gene expression. High-resolution confocal and super-resolution microscopy will support structural and spatial analysis of TRPC channels. Machine learning–based image analysis will be developed to quantify Ca2+ dynamics in tissue remodeling.
This project offers exceptional interdisciplinary training at the interface of vascular biology, ion-channel physiology, advanced imaging, and bioinformatics-supported image analysis. The PhD candidate will gain hands-on experience in both mouse and human systems, ensuring strong translational relevance.
References
1. Weissmann N et al. Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange Proc Natl Acad Sci USA. (2006). doi: 10.1073/pnas.0606728103;
2. Malczyk et al. Classical transient receptor potential channel 1 in hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med. (2013). doi: 10.1164/rccm.201307-1252OC.
People Involved
Primary supervisor: Andrea Olschewski
Collaborators: Chandran Nagaraj