Sengle, Gerhard - assoc. RG 21
New molecular mechanisms of fibrosis
Prof. Dr. Gerhard Sengle
Clinic for Pediatric and Adolescent Medicine
CMMC - assoc. RG 21
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Clinic for Pediatric and Adolescent Medicine
Joseph-Stelzmann-Str. 52
50931 Cologne
Introduction
Fibrosis is characterized by excess accumulation of extracellular matrix (ECM) components, leading to disrupted tissue function in affected organs. Fibrosis can develop in nearly every part of the body, and is an important driver of end-stage organ failure and death in a variety of chronic diseases. The high number of individuals affected by organ fibrosis and the associated morbidity and mortality shows the need for a better understanding of mechanisms involved in fibroblast activation and abnormal ECM deposition.
For the development of new therapeutic strategies to prevent or treat fibrotic disease it is mandatory to understand how individual ECM components integrate communication with the cell surface by presenting growth factors or providing fine-tuned biomechanical properties. In particular, the important role of epithelial–mesenchymal interactions in fibrosis needs to be elucidated. The goal of this proposal is to gain insight into newly uncovered molecular mechanisms of fibrotic reactions. We will specifically address the question how dysregulated epidermal-dermal communication is cause or consequence of fibrotic reactions.
Data from mouse models reflecting human fibrotic conditions revealed new critical determinants, including failed epidermal collagen chaperoning as well as TGF-β and lysyl oxidase ECM targeting. This proposal aims at providing a new understanding of the underlying molecular causes of fibrotic reactions which will lay the foundation for future translational approaches.
Clinical and Medical Relevance
Fibrosis is an important driver of organ failure and death. Despite intensive research, many aspects of the molecular causes of fibrosis remain unclear. Therefore, it is important to elucidate the molecular determinants crucial in the initiating steps of the disease.
By investigating new mouse models for organ fibrosis as well as corresponding patient cells in combination with structural and pharmacological approaches we will explore new therapeutic avenues to prevent or treat fibrotic disease.
Publications generated during 1/2023-12/2025 with CMMC affiliation
2024 (up to June)
- Zeyer KA, Bornert O, Nelea V, Bao X, Leytens A, Sharoyan S, Sengle G, Antonyan A, Bruckner-Tuderman L, Dengjel J, Reinhardt DP, and Nystrom A (2024). Dipeptidyl peptidase-4-mediated fibronectin processing evokes a pro-fibrotic extracellular matrix. J Invest Dermatol. doi:10.1016/j.jid.2024.03.020.
2023
- Godwin ARF, Dajani R, Zhang X, Thomson J, Holmes DF, Adamo CS, Sengle G, Sherratt MJ, Roseman AM, and Baldock C (2023). Fibrillin microfibril structure identifies long-range effects of inherited pathogenic mutations affecting a key regulatory latent TGFbeta-binding site. Nat Struct Mol Biol 30, 608-618. doi:10.1038/s41594-023-00950-8.
- Pankratz F, Maksudova A, Goesele R, Meier L, Proelss K, Marenne K, Thut AK, Sengle G, Correns A, Begelspacher J, Alkis D, Siegel PM, Smolka C, Grundmann S, Moser M, Zhou Q, and Esser JS (2023). BMPER Improves Vascular Remodeling and the Contractile Vascular SMC Phenotype. Int J Mol Sci 24. doi:10.3390/ijms24054950.
- Spanou CES, Wohl AP, Doherr S, Correns A, Sonntag N, Lutke S, Morgelin M, Imhof T, Gebauer JM, Baumann U, Grobe K, Koch M, and Sengle G (2023). Targeting of bone morphogenetic protein complexes to heparin/heparan sulfate glycosaminoglycans in bioactive conformation. FASEB J 37, e22717. doi:10.1096/fj.202200904R.