Meschis, Maria Martina
(2022)
Role of cell-surface receptor LRP1 in the development of lung fibrosis.
PhD thesis, University of Liverpool.
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Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease leading to a reduction of lung function, respiratory failure, and death. Around 3 million people are affected by IPF with a median survival after diagnosis of approximately 3 years. Currently there are no effective treatments available partly due to the incomplete understanding of molecular mechanisms that drive fibrosis through excessive accumulation of collagens, the hallmark of IPF. Low-density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitously expressed cell-surface receptor that is involved in many physiological roles. LRP1 mediates clathrin-dependent endocytosis of various molecules (LRP1 ligands) and modulates cellular signalling pathways. The relevance of LRP1 gene to lung function was discovered by a large genome-wide association study. However, little is known about its role in lung health and disease in vitro. In this study, the role of LRP1 in lung tissue in vivo was investigated using conditional Lrp1 knockout (KO) mice models. Since lung tissue consists of a variety of cell types, I first deleted Lrp1 in the whole body. Global deletion of Lrp1 gene in adulthood caused a rapid weight loss (>20%) and gastro-intestinal abnormalities, suggesting a crucial role of LRP1 in the digestion system and difficulty to use this mouse model to investigate the respiratory system. Among various lung cells, fibroblasts play a major role in collagen deposition. I thus specifically deleted Lrp1 in lung fibroblasts and challenged the mice with bleomycin to induce lung fibrosis. I discovered that excess collagen deposition was observed in control mice, whereas almost no collagen accumulation was detected in fibroblast-selective Lrp1 knockout mice. I also found that the inhibition of LRP1-mediated endocytosis induces cell death of various types of cells in vitro, highlighting the cytotoxicity of prolonged presence of LRP1 ligands. Finally, I identified molecules regulated by LRP1 in lung tissue by proteomics analysis. These findings shed light on novel in vivo roles of LRP1 that play a major role in the digestive system. Moreover, fibroblast LRP1 plays a crucial role in excess collagen deposition during the development of lung fibrosis. Identifying molecular mechanisms behind LRP1 function in collagen deposition may uncover new therapeutic approaches for lung fibrosis disease.
| Item Type: | Thesis (PhD) |
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| Divisions: | Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 16 Feb 2023 15:16 |
| Last Modified: | 16 Feb 2023 15:16 |
| DOI: | 10.17638/03168025 |
| Supervisors: |
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| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3168025 |
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