Drosophila model for muscular pain

Abstract

Olga's is fundamentally interested in how nerve cells remain healthy and functional throughout the live and during ageing. Olga uses in-vitro cell cultures, fruit flies and mice to understand how cells cope with metabolic stress challenges, like deprivation of growth factors and loss of ability to remove toxic debris. Most intriguing questions are how the nerve cells try to adapt to sustained stress and how this changes their function and communication towards other cells in a possibly adverse way. Such adjustments are believed to go wrong in chronic pain conditions resulting in maladaptation. The nerve cells, which receive information from other organs, become over-sensitive and show a stronger tendency to respond to stimuli, which normally would not trigger a healthy system. During her fellowship Olga will use the fruit fly Drosophila melanogaster to study how defects in the muscle provoke maladaptation in the nerve cells. She will concentrate on specific factors which respond to metabolic stress and then change the activity of the nerve cells. The very specific abilities of those factors will be exploited to make pain visible in the fruit fly. The success of this study will give novel insights on maladaptive communication and misinterpretation of pain signals and provide a new model to substitute mouse studies in search for novel pain genes and therapeutics. Drosophila as a traditionally powerful genetic model offers an excellent platform to understand basic mechanisms and brings an extraordinary advantage compared to mice through a shorter lifespan. The uptake of the fruit fly as a model for chronic pain in the wider research community and industry would facilitate and accelerate the efforts to develop therapeutic approaches, ideally, aiming at re-establishment of the balance in the nerve cells, provoking them to re-learn to not interpret mild stimuli as pain.

Technical Summary

Maladaptive homeostatic plasticity, as a consequence of non-cell autonomous insults, is one of the central aspects in chronic pain studies, where changes in excitability in the nociceptive system, such as sensory neurons, occur following a damaging insult elsewhere. Rbfox splicing factor family regulates genetic output of muscles and neurons by mediating alternative splicing and mRNA degradation. The ability of Rbfox family to respond to upstream activity changes and subsequently to regulate excitability and activity provide intriguing mechanisms for the adaptation of functional circuits to local environments resembling prerequisite characteristics for homeostatic plasticity. Preliminary data and literature suggest that Rbfox splicing may be involved in sensory neuron sensitization. The proposed study aims to establish Drosophila models to understand the role of Rbfox in sensorimotor circuit homeostasis, with particular focus on balance between the muscle and sensory neuron function. These Drosophila models, which allow monitoring Rbfox activity, will be tested for their potential to serve as a novel, so far unrepresented, sensor tool to study non-cell autonomous sensory neuron sensitization in chronic conditions affecting the skeletal muscle. The substantial functional consequences, like changes in mRNA splicing, translation and degradation as well as miRNA metabolism, upon altered Rbfox activity would provide complementary advantages to tools like calcium sensors. The power of the model will be demonstrated by subsequent analysis of genes already known to participate in mediation of chronic pain as well as known Rbfox targets, linked to sensory neuron sensitization. The relevance to inflammatory response and ability of the model to replace moderate severity limit protocols, such CFA-injection in the muscle of mice for studies of chronic inflammatory pain mechanisms, will be examined.

Publications

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