Welcome to the Klimaschewski lab
'Understanding how the brain works is the most interesting and challenging question in the universe' (David Nutt)
The study of the morphological basis of neuronal function remains a subject of tremendous fascination and a key to better understanding of the nervous system. Unraveling the variety of neuronal circuits and their interactions with peripheral sensors and effector organs is as much relevant now as it was over 100 years ago in the time of Golgi and Cajal. Neural tract tracing, cell lineage mapping or the study of morphological plasticity of dendritic spines and axonal arbors all require advanced neuromorphological and imaging techniques.
The Division of Neuroanatomy at the Medical University of Innsbruck contributes to this endeavour by offering lectures and seminars in functional as well as comparative Neuroanatomy for MD and PhD students.
As Gerald Edelman, the American biologist who received the 1972 Nobel Prize in Physiology or Medicine for work on the immune system, once wrote: "If someone held a gun to my head and threatened oblivion if I did not identify the single word most significant for understanding the brain, I would say 'neuroanatomy'. Indeed, perhaps the most important general observation that can be made about the brain is that its anatomy is the most important thing about it."
However, as Georg F. Striedter in his insightful book 'Principles of Brain Evolution' puts it, "reconstructions ... are interesting and important but, ultimately, they are not enough. Henri Poincaré, the French mathematician and philosopher, clearly expressed this sentiment: 'Science is built with facts, as a house is built with stones; but a collection of facts is no more a science than a pile of stones is a house ... Above all, the scientist must make predictions.'"
Our research addresses the morphological consequences of growth factor signaling and receptor tyrosine kinase trafficking in the nervous system. Applying mainly cellular methods combined with high-resolution imaging, we are studying fundamental neurobiological phenomena such as neurite outgrowth and glial proliferation. Fibroblast growth factor (FGF) receptor signaling is in the focus of our projects. We have demonstrated that blocking FGF induced negative feedback inhibitors such as Sprouty2 promotes axon regeneration and neuronal survival in neurological disease models of the peripheral and central nervous system.
Signaling integrators in neurons and glial cells
Neurotrophic factors and their receptors have been in the focus for the development of therapeutic treatments for neurological and psychiatric disorders over many years. Unfortunately, growth factor therapies have been largely unsuccessfull in the past. It became clear that receptor tyrosine kinases and their signaling pathways may not be sufficiently activated in the aging brain to exert significant neuroprotective, neurorestorative and stimulatory effects on diseased neurons (possibly due to receptor down-regulation or truncation). Therefore, the aim of our laboratory is to identify intracellular signaling molecules downstream of RTKs which may act as pharmacological targets to increase pro-survival and pro-regenerative mechanisms in the diseased peripheral and central nervous system.
Sprouty proteins form a small family of negative feedback inhibitors of growth factor induced intracellular signaling, in particular, the RAS/RAF/MEK/ERK pathway. In the nervous system, down-regulation or knock-out of Sprouties promotes recovery from mechanical, vascular or excitotoxic brain lesions. Applying three different in vivo lesion models we demonstrated that reduction of Sprouties in neurons and glial cells improves neuronal survival and axonal regeneration in the central and peripheral nervous system.
We have shown that primary sensory neurons dissociated from Sprouty2 knock-out ganglia exhibit elevated ERK activity and enhanced axon outgrowth. Following sciatic nerve crush, significantly more myelinated axons regenerate in Sprouty2+/- mice which is accompanied by faster recovery of sensomotor performance, higher number of motor endplates in distal muscles and increased expression of GAP-43 (Marvaldi et al. 2015).
With regard to the CNS, injections of siRNAs against Sprouties into rat brains reduce the lesion size in response to endothelin-induced vasoconstriction (a model for stroke, Klimaschewski et al. 2015). In another CNS lesion model, kainate-induced epileptogenesis, secondary brain damage is significantly diminished in Sprouty2/4 heterozygous knockouts. These mice exhibit less neuronal loss than their wildtype littermates after kainate injection into the hippocampus which is accompanied by reduced neuronal migration (dispersion of granule cells) and increased astroglial proliferation (Thongrong et al. 2016). Currently, we are investigating the role of Sprouty2 in astrocyte and glioma signaling and proliferation in more detail.