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

耳保护机制：Survivin-NO-信号传导对人工耳蜗植入后微循环和听力保护的影响

• 批准号: 325911239
• 负责人: Professor Dr. Sebastian Strieth
• 金额: --
• 依托单位: Forschungsgruppe Molekulare und zelluläre Onkologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/325911239?language=en
• 关键词: Mechanisms; otoprotection; Impact; Survivin; NO

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.

尽管采用了微创电极植入、保留结构的手术技术和术中使用糖皮质激素，听力残障患者的耳蜗植入术仍可能导致部分或完全丧失残余听力。潜在的分子机制尚不完全清楚，尽管这对耳保护策略的发展至关重要。在我们之前的工作中，我们令人信服地表明，微循环损伤以及亚硝化应激诱导的对细胞保护机制的干扰与内耳损伤有关。一氧化氮（NO）可调节螺旋神经节和耳蜗侧壁细胞保护抑制剂-凋亡蛋白Survivin的表达，从而维持Corti器官的功能性微循环。survivin - no轴对hCI插入损伤后微循环和听力功能的影响及其潜在的信号通路及其最终的耳保护或耳毒性相关性尚未被研究。基于我们之前的研究，我们假设hCI影响耳蜗外侧壁，导致微循环障碍以及eNOS/ inos驱动的NO诱导，调节Survivin的表达。这些应激条件可能最终导致听力功能受损。因此，我们将研究微循环和survivin - no信号在hCI中的作用。项目目标是：(1)监测微循环和听力功能；(2) hci诱导内皮细胞活化和NO诱导的测定；(3)剖析hCI-/ no相关的survivin调节信号级联的影响(4)靶向survivin抑制与hCI相关听力损伤的相关性；(5) hci对听力、微循环、内皮细胞活化、NO诱导及survivin相关耳保护蛋白表达影响的统计相关分析；(6)与局部糖皮质激素治疗相比，通过局部NO抑制或诱导来调节survivin -NO信号以及全身吸入NO应用作为hCI中耳保护的新策略。我们将使用我们所建立的动物模型，正常听力的豚鼠，对耳蜗侧壁进行分析，并辅以基础电极插入，以及条件生存素敲除小鼠模型。实验包括听力测定、活体荧光显微镜、survivin靶向脂质体纳米载体的应用、免疫组织化学和激光捕获显微解剖。该项目不仅将揭示关键的hci相关耳部保护机制，还可能为临床中新的耳部保护策略开辟转化前景。