In this project, the PhD-student will work on assessing the role of TRP channels in pulmonary fibrosis, a chronic progressive lung disease. Strategies aimed at modulation of TRP channels will be tested for potential anti-fibrotic effects in vivo, ex vivo and in vitro. This is of special interest as current therapeutics have limited efficacy and novel drugs are urgently needed.
Project Details
Background:
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with a median survival of only 3-4 years, significantly shorter than many types of cancer. It is characterized by exaggerated extracellular matrix (ECM) deposition in the lungs, loss of alveolar tissue and disrupted gas exchange. Currently, there are only two therapeutic options for the treatment of IPF, pirfenidone and nintedanib. While these drugs slow disease progression and might prolong survival, they are neither curative, nor do they entirely stop loss of lung function. Furthermore, a significant proportion of patients discontinue anti-fibrotic therapy due to side effects. Therefore, other therapeutic options are urgently needed.
Transient Receptor Potential Canonical channel Isoform (TRPC)1 is a non specifc ion channel located on plasma mebranes. TRPC1 has been shown to mediate myofibroblast transdifferetiation and fibroblast proliferation, two hallmarks of pulmonary fibrosis. We found that TRPC1 shows highest expression of all TRP channels in fibroblasts from IPF patients.
Hypothesis and Objectives:
Due to our preliminary data, we know that TRPC1 shows highest expression of all TRP channels in fibroblasts from IPF patients and thus hypothesize that it may be a novel therapeutic target in IPF. We want to assess whether (I) TRPC1 modulation has therapeutic potential in PF of different etiologies (II) which mechanisms and cells mediate these effects and (III) whether TRPC1 modulation is able to revert fibrosis.
Methodology:
We will use bleomycin and TGF-beta transgenic mouse models of PF to test effects of TRPC1 modulation and KD and assess fibrosis using hydroxyproline test, Ashcroft scoring, and lung function test. Fibroblasts and alveolar epithelial cells will be used for cell culture experiments, followed by ELISA, qPCR and WB to detect DES effects on for example ECM production, lipofibroblast differentiation or survival associated pathways. We will investigate proliferation/apoptosis via EDU/Ki67 and AnnexinV/PI/activated caspase3 staining respectively, cell counts and caspase 3/7 activity. Precision cut lung slices (PCLS) from PF patients of different etiology and healthy controls will be treated with DES. Readouts will include safety and pharmacokinetics (mouse models), respective pathways/affected cells (RNASeq, sc/sn-RNASeq) including validation and morphometry (microscopy/immunofluorescence).
References
- Rajesh, R; Mooslechner, AA; Schweighofer, H; Pahernik, S; Lanz, I; Atallah, R; Platzer, W; Aigner, C; Benazzo, A; Angiari, S; Marsh, L; Kwapiszewska, G; Heinemann, A; Bärnthaler, T; Succinate aggravates pulmonary fibrosis through the succinate/SUCNR1 axis.
- Am J Physiol Lung Cell Mol Physiol. 2025;
- Shuni Li, Lihui Qu, Lifen Zhou, Na Zhan, Linmei Liu, Yuquan Ling, Qingzi Chen, Wuping Lai, Nan Lin, Jianhua Li,; Biomass fuels related-PM2.5 promotes lung fibroblast-myofibroblast transition through PI3K/AKT/TRPC1 pathway, Ecotoxicology and Environmental Safety,2024,
- Kenichi Ikeda, Toshiaki Nakajima, Yumiko Yamamoto, Nami Takano, Tomofumi Tanaka, Hironobu Kikuchi, Gaku Oguri, Toshihiro Morita, Fumitaka Nakamura, Issei Komuro,
- Roles of transient receptor potential canonical (TRPC) channels and reverse-mode Na+/Ca2+ exchanger on cell proliferation in human cardiac fibroblasts: Effects of transforming growth factor β1,; Cell Calcium, 2013,
- Rajesh, R; Atallah, R; Bärnthaler; Dysregulation of metabolic pathways in pulmonary fibrosis
- T, Pharmacology and Therapeutics 2023; 246: 108436
People Involved
Primary supervisor: Thomas Bärnthaler