Center for Molecular Medicine Cologne

Gerhard Sengle - assoc. RG 21

New molecular mechanisms of fibrosis

Abstract

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.

Project Related Publications

  1. Zigrino P, and Sengle G. Fibrillin microfibrils and proteases, key integrators of fibrotic pathways. Adv Drug Deliv Rev. (2019) 146:3-16.
  2. Schiavinato A, Keene DR, Imhof T, Doliana R, Sasaki T, Sengle G. Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts. Sci Rep. (2017) 7, 5526.
  3. Brauchle E, Bauer H, Fernes P, Zuk A, Schenke-Layland K, Sengle G. Raman microspectroscopy as a diagnostic tool for the non-invasive analysis of fibrillin-1 deficiency in the skin and in the in vitro skin models. Acta Biomater. (2017) 52, 41-48.
  4. Sengle G, Sakai LY. The fibrillin microfibril scaffold: A niche for growth factors and mechanosensation? Matrix Biol, 2015, 47, 3-12.
  5. Wohl AP, Troilo H, Zuk AV, Collins R, Baldock C, Sengle G. Extracellular regulation of BMP activity by the microfibril component fibrillin-1. J Biol Chem. (2016) 291, 12732-46.
  6. Schiavinato A, Keene DR, Wohl AP, Corallo D, Colombatti A, Wagener R, Paulsson M, Bonaldo P, Sengle G. Targeting of EMILIN-1 and EMILIN-2 to fibrillin microfibrils facilitates their incorporation into the extracellular matrix. J Invest Dermatol. (2016) 136, 1150-1160.
  7. Sengle G, Carlberg V, Tufa SF, Charbonneau NL, Smaldone S, Carlson EJ, Ramirez F, Keene DR, Sakai LY. Abnormal Activation of BMP Signaling Causes Myopathy in Fbn2 Null Mice. PLoS Genet. (2015) 11, e1005340.
  8. Sengle G, Tsutsui K, Keene DR, Tufa SF, Carlson EJ, Charbonneau NL, Ono RN, Sasaki T, Wirtz MK, Samples JR, Fessler LI, Fessler JH, Sekiguchi K, Hayflick SJ, Sakai LY. Microenvironmental regulation by fibrillin-1. PLoS Genet (2012) 8, e1002425.
Prof. Dr. Gerhard Sengle CMMC Cologne
Prof. Dr. Gerhard Sengle

Institute for Biochemistry II

CMMC - assoc. Research Group

+49 221 478 97260

+49 221 478 6977

Institute for Biochemistry II

Joseph-Stelzmann-Str. 52

50931 Cologne

http://www.uni-koeln.de/med-fak/biochemie/staff/sengle/

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Gerhard Sengle

Link to PubMed

Group Members

Dr. Katrin Hildebrandt
Christin Adamo
Chara Spanou
Laura-Marie Zimmermann
Annkatrin Correns
Steffen Lütke
Yousef Morcos