Project Details
Projekt
Initiation, propagation and molecular integration of physiological and pathological redox signals in neurons
Subject Area
Biochemistry
Term
from 2014 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 251955167
Redox-based signals are emerging as new second messenger pathways that regulate cellular behaviour in many parts of the body, including in the nervous system. Still the mechanistic basis of the redox signals that occur in neurons and their axons and synapses, and how these signals influence neuronal function and survival is currently not well understood. We have now developed novel approaches for imaging neuronal redox signals in the intact nervous system based on the transgenic expression of recently developed genetically encoded redox indicators combined with in vivo microscopy techniques. These approaches allow us (1) to follow redox signals in individual axonal mitochondria with high temporal and spatial resolution both in the peripheral and central nervous systems; (2) to use multi-parametric imaging to correlate redox signals with changes in mitochondrial membrane potential and pH, as well as with axonal and mitochondrial calcium levels; (3) to employ targeted pharmacological and genetic manipulations to dissect the molecular mechanisms that underlie these signals. Such in vivo imaging has revealed that highly dynamic redox signals can be induced in axonal mitochondria both by physiological challenges, such as increased neuronal activity, as well as by pathological challenges, such as crush or contusion lesions. In the proposed project we now want to use multi-parametric in vivo imaging of activity-dependent (Aim1) and injury-induced (Aim2) redox signals to better understand: (1) when and where neuronal redox signals are initiated and how they travel along axons; (2) how such redox signals are integrated with parallel streams of physiological and pathological calcium signals to modulate axonal function and survival; and (3) whether the mechanistic analysis of physiological and pathological redox changes can identify thiol switches that allow targeting pathological redox alterations, while leaving physiological redox signalling intact. We believe that such a refined understanding of when, where and how disease-related redox signals arise is required for the design of tailored "redox-modifying" strategies that can limit neuronal damage caused by redox dysregulation in traumatic, inflammatory and degenerative conditions of the nervous system.
DFG Programme
Priority Programmes
