Mechanisms of otoprotection: Impact of Survivin-NO-signaling on microcirculation and hearing preservation after cochlear implantation

• Applicant: Professor Dr. Sebastian Strieth
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325911239

In spite of minimal-invasive electrode insertion, structure-preserving surgical techniques and intraoperative glucocorticoid application, cochlea implantation in patients with hearing remnants (hCI) may still result in partial or complete loss of residual hearing. The underlying molecular mechanisms are still incompletely understood, though key for the development of otoprotective strategies.In our previous work, we convincingly showed that microcirculatory impairment as well as nitrosative stress-induced interference with cytoprotective mechanisms are involved in inner ear damage. Nitric oxide (NO) was found to modulate the expression of the cytoprotective inhibitor-of-apoptosis-protein Survivin in the spiral ganglion as well as in the cochlear lateral wall, hosting the functional microcirculation of the Organ of Corti. The impact and underlying signaling pathways of the Survivin-NO-axis on microcirculation and hearing function following hCI insertion trauma as well as their ultimate otoprotective or ototoxic relevance have not yet been investigated.Based on our previous studies, we hypothesize that hCI affects the lateral cochlear wall, resulting in microcirculatory disturbance as well as to an eNOS/iNOS-driven NO induction, modulating the expression of Survivin. These stress conditions may ultimately contribute to impairment of hearing function. Hence, the role of microcirculation and Survivin-NO-signaling for hCI shall here be investigated. Project aims are: (1) monitoring microcirculation and hearing function; (2) measurement of hCI-induced endothelial cell activation and NO induction; (3) dissecting the impact of hCI-/NO-associated Survivin-modulating signaling cascades (4) relevance of targeted survivin inhibition for hCI-associated hearing impairment; (5) statistical correlation analysis of hCI-associated effects on parameters of hearing, microcirculation, endothelial cell activation, NO induction as well as on the expression of Survivin-associated otoprotective proteins; (6) modulation of Survivin-NO-signaling using local NO-inhibition or -induction as well as systemic inhalative NO application as a novel otoprotection strategy in hCI compared with local glucocorticoid treatment.We will use our established animal model, the normal hearing guinea pig, for analysis of the lateral cochlear wall complemented by basal electrode insertion as well as a conditional survivin-knock out mouse model. Experiments involve audiometry, in-vivo-fluorescence microscopy, application of Survivin-targeting liposomal nanocarriers, immunohistochemistry, and laser capture-microdissection.The project will not only uncover fundamental crucial hCI-associated otoprotective mechanisms but may also open translational vistas for novel otoprotection strategies in the clinics.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Roland H. Stauber