Transcriptomic analysis and validation of neuroprotective candidates for the development of innovative diagnostic and therapeutic targets in neurology

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This research proposal aims to identify neuroprotective candidates by transcriptome analysis of injured neurons, for the development of innovative diagnostic and therapeutic targets in neurology. To date, clinical neurology suffers from the blatant situation that the majority of both acute and chronic CNS disorders cannot be treated in a curative or causal fashion. Importantly, most neurological diseases share one striking similarity: the death of neuronal cells is what produces malfunctions and symptoms in affected individuals. This is why one solving strategy would be the prevention, or at least the delay, of neuronal death while a harmful stimulus risks the survival of neurons. Armed with a better understanding of how neurons mechanistically react to survival-threatening injuries, the field of neuroprotection and neurology could be positively transformed. With appropriate knowledge of signaling events that are beneficial and detrimental for the cell fate, appropriate and selective therapeutic interference might be able to prolong cell survival and to prevent cell death. Data from various preconditioning experiments and selective neuronal vulnerability already provide biological evidence that this is attainable. However, little is known about the exact molecular mechanism that takes place in neurons after injury or damage. By performing a combination of separate transcriptome analyses by means of RNA sequencing; where three independent models of neurodegeneration are used to determine a common transcriptomic signature shared by newly injured neurons, this research proposal aims to identify key components and potentially druggable targets of neuron damage response. To validate the sequencing results derived from murine primary cortical neurons, the animal model C. elegans will be applied; taking advantage of the easy and established tools to establish genetically modified animals and the ability to perform neuron injury experiments at the single-cell level in vivo. The striking advantage of this research project is the fact that we have performed transcriptome analysis from mammalian tissue and will transfer the results a step back in evolutionary terms. This means that all validated neuroprotective candidates automatically have a mouse homologue and can be applied in a mammalian test system at a later time point. Long-term, the goal of this research proposal is to decipher fundamental mechanisms of neuronal damage that could be useful in the diagnosis and therapy of a variety of neurological disorders. By finding genes or proteins with a highly specific expression in stressed neuronal cells (neurons at risk), it would not just be possible to create new biological tools and animal models for further research, but also to develop techniques that could improve the diagnosis and the staging of brain disorders.