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Wachstumsfaktoren im Gehirn

Wachstumsfaktoren und ihre Bindungsstellen (Rezeptoren) an Nerven- und Gliazellen spielen im Nervengewebe eine herausragende Rolle während der Entwicklung und bei verschiedensten Erkrankungen des Gehirns. Wir forschen insbesondere über die Fibroblasten-Wachstumsfaktoren (FGFs), die auch im Nervengewebe vorkommen. Sie binden an spezielle Rezeptoren (Tyrosin-Kinasen), deren intrazelluläre Signal- und Transportwege unter normalen und pathologischen Bedingungen in unserem Labor analysiert werden.

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Growth Factors in the Brain

Fibroblast growth factors (FGFs) are important for the development and repair of the nervous system. Stimulation of FGF receptors promotes neurogenesis, neuronal protection, axonal regeneration and remyelination in the injured nervous system. Our research focuses on the signalling and transport of FGFR type 1, the predominant FGF receptor in the nervous system (Csanaky et al. 2019). The inhibition of endocytosis and enhanced recycling of this receptor tyrosine kinase exert a significant influence on neuronal survival and axon outgrowth (Hausott et al. 2019).

Among the negative feedback inhibitors of FGFR1-induced signalling are the Sprouty proteins that comprise a family of four homologous molecules. Down-regulation of Sprouty 2 and 4 promotes recovery from mechanical, vascular or excitotoxic brain lesions. Applying three different in vivo lesion models, we have demonstrated that the reduction of Sprouties in neurons or glial cells improves neuronal survival and axonal regeneration in the central and peripheral nervous system.

We have shown that primary sensory neurons dissociated from heterozygous Sprouty 2 knock-out mice exhibit elevated MAP kinase (ERK) activity and enhanced axon outgrowth in response to nerve injury. Following sciatic nerve crush, significantly more myelinated axons regenerate in mice with reduced Sprouty 2 levels, accompanied by faster recovery of function and increased expression of GAP-43 (Marvaldi et al. 2015). We also investigated a combined approach to promote long-distance axon growth in primary neuronal cell culture: dual-interference with Sprouty 2 and PTEN, an inhibitor of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Our results clearly show that their simultaneous knockdown in neurons promotes axon elongation more strongly than the knockdown of each molecule individually (Jamsuwan et al. 2020).

With regard to the CNS, the injection of siRNAs against Sprouties into rat brains reduces the lesion size in response to endothelin-induced vasoconstriction (a model for stroke, Klimaschewski et al. 2016). Secondary brain damage is also significantly diminished in mice with reduced Sprouty 2/4 levels. In response to kainate-induced excitotoxicity in the hippocampus, neuronal survival and reactive astrogliosis are enhanced in heterozygous Sprouty 2/4 knock-outs by comparison with their wild-type littermates (Thongrong et al. 2016).

Furthermore, Sprouty 2 is a key regulator of tumour formation in the brain (Park et al. 2018). It is up-regulated in malignant gliomas and this correlates with reduced survival in patients. Knockdown of Sprouty 2 dramatically inhibits glioblastoma growth and increases EGF-induced ERK and AKT activation concomitant with premature S-phase entry of tumour cells. Consistent with these findings, DNA damage response and cytotoxicity are increased.

Taken together, treatment with FGFs and interference with Sprouties may provide a novel therapeutic strategy to increase and prolong growth factor signalling in the lesioned peripheral nervous system and in the diseased brain. For further information please see our review articles on the role of Sprouties (Hausott and Klimaschewski 2018) and FGFs in the nervous system (Klimaschewski and Claus 2021).

Funding

Austrian Science Fund (FWF), Tyrol Science Fund and MUI-START

Institute of Neuroanatomy

 

Prof. Dr. med. Lars Klimaschewski

Medical University Innsbruck
Department of Anatomy & Histology
Institute of Neuroanatomy
Muellerstrasse 59
6020 Innsbruck, Austria
 
TEL +43 512 9003 71160
FAX +43 512 9003 73170
Email: lars.klimaschewski@i-med.ac.at
 

 

Prof. Dr. med. Lars Klimaschewski

Medical University Innsbruck
Department of Anatomy & Histology
Institute of Neuroanatomy
Muellerstrasse 59
6020 Innsbruck, Austria
 
TEL +43 512 9003 71160
FAX +43 512 9003 73170
Email: lars.klimaschewski@i-med.ac.at