Metabolic adaptation in injuries of the peripheral nervous system

Descripción del proyecto

Estudio de los secretos metabólicos de la regeneración nerviosa

Las neuropatías periféricas, trastornos neurológicos frecuentes pero en gran medida sin cura, constituye todo un reto sanitario. El sistema nervioso periférico posee una gran capacidad regenerativa, pero la recuperación total tras un traumatismo nervioso es poco frecuente. El éxito de la regeneración nerviosa depende de la coordinación de los procesos de degeneración y regeneración de los gliocitos de los nervios periféricos, que tienen que hacer frente una mayor demanda metabólica. En la diabetes y la obesidad, el estrés metabólico crónico agrava estos problemas y da lugar a neuropatías. En este contexto, el proyecto NervAdapt, financiado por el Consejo Europeo de Investigación, se centra en la singular adaptabilidad metabólica de las células de Schwann, que desempeñan un papel fundamental en la regeneración nerviosa. En el proyecto se estudiará la gestión de la demanda energética durante una lesión nerviosa en las células de Schwann. NervAdapt esclarecerá cómo los gliocitos mantienen la homeostasis y se adaptan al estrés metabólico, una información que podría mejorar los tratamientos de las neuropatías.

Objetivo

The peripheral nervous system constitutes a prime example of a tissue with a strong regenerative potential. Full recovery upon nerve trauma, however, is rare and usually fails in peripheral neuropathies - common, yet largely untreatable neurological disorders. Nerve repair strictly depends on the orchestration of both nerve de- and regeneration by peripheral nerve glial cells, which need to overcome a substantial metabolic challenge in injury. NervAdapt is based on the fundamental premise that Schwann cells, in the course of evolution, developed an exceptional metabolic adaptability to ensure repair. Capitalizing on acute nerve injury as a prototypic model system to explore conserved repair mechanisms, we aim to unveil glial metabolic adaptation to increased energetic demands and distinct substrate availabilities. A central goal of NervAdapt is to elucidate how glial homeostasis is integrated in a fine-tuned cellular network that extends to interactions with neighbouring tissue compartments. Employing elaborated genetic mouse models, 3D electron microscopy, and leading-edge spatial and single cell to organ level profiling approaches, NervAdapt will pioneer to generate a comprehensive multi-level framework of the nerve injury response. Chronic metabolic stressors, such as in diabetes and obesity, in turn, may lead to a constant glial overstimulation and compromise glial metabolic homeostasis. Metabolically induced neuropathies indeed underscore the specific vulnerability of the peripheral nervous system to a systemic metabolic burden. Within NervAdapt we follow the hypothesis that a persistently perturbed metabolic homeostasis causes molecular and cellular glial metabolic inflexibility, ultimately driving metabolic neuropathy. Together, NervAdapt seeks to identify key checkpoints of glial metabolic (mal-)adaptation under energy demand and metabolic load, revealing a new dimension of metabolic adjustment at the nerve organ level.