Gerhard Sengle / Raimund Wagener / Mats Paulsson - C 14

Extracellular microfibrillar systems in disease pathogenesis: functional interactions in cytokine regulation, cellular differentiation and tissue homeostasis

Abstract

New strategies for treating congenital muscular dystrophies are needed. Current treatments are limited and aim to prolong ambulation and survival. Since most of the genes and mechanisms responsible for congenital muscular dystrophies are still unknown, elucidation of these genes and their molecular function may provide new insights that can lead to novel treatments. Cellular microenvironments such as stem cell niches in muscle are defined by extracellular microfibrillar networks (EMFN) which are required for muscle structure and function. EMFN made of fibrillin-1 and -2, and collagen VI with associated ligands are of particular interest since human mutations in EMFN components result in myopathies with overlapping clinical features. Our working hypothesis is that EMFN function in concert to actively regulate spatial concentration, and bioavailability of cytokines. This may be accomplished by concentrating specific adaptor molecules, co-receptors, or activating enzymes. We will test this hypothesis in mice lacking critical building blocks of EMFN with regard to perturbation of tissue architecture, cytokine levels and activity, as well as functional consequences for cells in the course/progression of disease. Analyzing biopsies from well-defined patient cohorts will test the relevance of our concept for human disease. This work has the potential to provide a comprehensive and fundamental understanding of the molecular pathomechanisms caused by mutations in EMFN components which will lay the foundation for future translational approaches of congenital muscular dystrophies.

Clinical/medical relevance and sustainability in disease understanding

It has been estimated that only half of the congenital muscular dystrophies can be ascribed to known defects. Therefore, it remains important to identify additional muscular dystrophy disease genes, especially if these might lead to novel pathogenetic mechanisms common to at least some of the muscular dystrophies. Common pathogenetic targets might then lead to new opportunities to develop better treatments. Treatment of EMFN deficient mice or patient cells will let us explore these avenues.

Selected publications

Maaß, T., Bayley, C.P., Mörgelin, M., Lettmann, S., Bonaldo, P., Paulsson, M., Baldock, C.*, and Wagener, R.* (2016). Heterogeneity of collagen VI microfibrils: Structural analysis of non-collagenous regions, J. Biol. Chem. 291, 5247-5258. *equal contribution.

Wohl, A.P., Troilo, H., Collins, R.F., Baldock, C., Sengle, G. (2016). Extracellular regulation of bone morphogenetic protein activity by the microfibril component fibrillin-1. J. Biol. Chem. 291, 12732-46.

Schiavinato, A., Keene, D.R., Wohl, A.P., Corallo, D., Colombatti, A., Wagener, R., Paulsson, M., Bonaldo, P.*, Sengle, G.* (2016). Targeting of EMILIN-1 and EMILIN-2 to fibrillin microfibrils facilitates their incorporation into the extracellular matrix. J. Invest. Dermatol. 136, 1150-1160. * equal contribution.

Becker, A.K.§, Mikolajek, H. §, Paulsson, M., and Wagener, R.*, Werner, J.M.* (2014) A novel structure of a collagen VI VWA-domain displays N- and C-termini at opposite sides of the protein. Structure 22, 199-208. § and * equal contribution.

Sengle, G., Carlberg, V., Tufa, S.F., Charbonneau, N.L., Smaldone, S., Carlson, E.J., Ramirez, F., Keene, D.R., Sakai, L.Y. (2015). Abnormal activation of BMP signaling causes myopathy in Fbn2 null mice. PLoS Genet. 11, e1005340.


PD Dr. rer. nat. Gerhard Sengle

Institute for Biochemistry II

PD Dr. rer. nat. Gerhard Sengle

Principal Investigator C 14

gsengle@uni-koeln.de

Work +49 221 478 97260

Fax (Work) +49 221 478 6977

Institute for Biochemistry II
Joseph-Stelzmann-Str. 52
50931 Cologne

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

Publications - Gerhard Sengle

Link to PubMed


Prof. Dr. rer. nat. Raimund Wagener

Institute for Biochemistry II

Prof. Dr. rer. nat. Raimund Wagener

Co-Principal Investigator C 14

raimund.wagener@uni-koeln.de

Work +49 221 478 6990

Fax (Work) +49 221 478 6977

Institute for Biochemistry II
Joseph-Stelzmann-Str. 52
50931 Cologne

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

Publications - Raimund Wagener

Link to PubMed


Prof. Dr. rer. nat. Mats Paulsson

Institute for Biochemistry II

Prof. Dr. rer. nat. Mats Paulsson

Co-Principal Investigator C 14
Executive Board Member

mats.paulsson@uni-koeln.de

Work +49 221 478 6997

Fax (Work) +49 221 478 6977

Institute for Biochemistry II
Joseph-Stelzmann-Str. 52
50931 Cologne

http://www.uni-koeln.de/med-fak/biochemie/biomed2/

Publications - Mats Paulsson

Link to PubMed

Group Members

Ann-Kathrin Becker (former PhD student)
Stefanie Heumüller (PhD student)
Katrin Hildebrandt (PhD student)
Tobias Maaß (former PhD student)
Alvise Schiavinato (guest scientist)
Alexander Wohl (former PhD student)