Identificazione di nuovi target terapeutici per il trattamento delle neurodegenerazioni sensoriali dell'orecchio

Hearing loss represents the fourth cause of disability in the world according to the Global Burden of Disease Study, and the number of affected patients is expected to increase in the next years. The absence of effective therapies for the treatment of sensorineural hearing loss leads to irreversible deafness and calls for an urgent need of new therapeutic approaches. To make improvements in the field, in this dissertation, we investigated the effects of recombinant human nerve growth factor (rhNGF) and recombinant human brain derived neurotrophic factor (rhBDNF) on sensory and non-sensory cells of the organ of Corti. To this purpose, the experiments have been conducted by three partners in the framework of the “PON ricerca e innovazione”: the University of L’Aquila (L’Aquila, Italy), Dompé Farmaceutici S.p.A (Naples, Italy), and University Medical Center (UMC) Utrecht (Utrecht, The Netherlands). The first objective of the project was the investigation of the miRNAs profiles induced by rhNGF and rhBDNF in vitro on murine cochlear cells derived from the organ of Corti. The subsequent in silico analysis allowed us to identify a wide spectrum of target genes and signalings by the modulated miRNAs. Importantly, many of the target pathways by both neurotrophins involved cell survival, proliferation, neuronal differentiation and metabolic pathways. As a second step, we investigated the effects of rhNGF and rhBDNF on the survival of sensory and non-sensory cells of the organ of Corti of ototoxically deafened guinea pigs, and found limited effects in terms of cell number by both the treatments. At this level, we did not take into account any other aspects, such as the molecular events underlying the activity of those cells, that could affect their function. We therefore moved to molecular investigations in the organ of Corti of deafened guinea pigs. We selected the mTOR signaling from the in vitro and in silico analysis. Since the mTOR signaling was predominantly modulated by rhBDNF, we limited our investigations to this neurotrophin. We found that the BDNF-treated organs of Corti from deafened guinea pigs presented increased levels of pmTOR compared to normal hearing ears, and increased levels of mTOR compared to both untreated and normal hearing cochleas. On this basis, it is possible that rhBDNF may exert a protective effect on the organ of Corti that is mainly associated with the molecular function of those cells and not appreciable in terms of cell number. In conclusion, this dissertation provides a comprehensive overview over the effects of rhNGF and rhBDNF in the organ of Corti, and lays the foundation for the identification of new therapeutic targets.