de Vries Ines, Schmitt Heike, Lenarz Thomas, Prenzler Nils, Alvi Sameer, Staecker Hinrich, Durisin Martin, Warnecke Athanasia
Department of Otolaryngology, Hannover Medical School, Hanover, Germany.
Cluster of Excellence Hearing4all, German Research Foundation, Hannover Medical School, Hanover, Germany.
Front Neurosci. 2019 Mar 26;13:214. doi: 10.3389/fnins.2019.00214. eCollection 2019.
The outcome of cochlear implantation depends on multiple variables including the underlying health of the cochlea. Brain derived neurotrophic factor (BDNF) has been shown to support spiral ganglion neurons and to improve implant function in animal models. Whether endogenous BDNF or BDNF-regulated proteins can be used as biomarkers to predict cochlear health and implant outcome has not been investigated yet. Gene expression of BDNF and downstream signaling molecules were identified in tissue of human cochleae obtained from normal hearing patients ( = 3) during skull base surgeries. Based on the gene expression data, bioinformatic analysis was utilized to predict the regulation of proteins by BDNF. The presence of proteins corresponding to these genes was investigated in perilymph ( = 41) obtained from hearing-impaired patients ( = 38) during cochlear implantation or skull base surgery for removal of vestibular schwannoma by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Analyzed by mass spectrometry were 41 perilymph samples despite three patients undergoing bilateral cochlear implantation. These particular BDNF regulated proteins were not detectable in any of the perilymph samples. Subsequently, targeted analysis of the perilymph proteome data with Ingenuity Pathway Analysis (IPA) identified further proteins in human perilymph that could be regulated by BDNF. These BDNF regulated proteins were correlated to the presence of residual hearing (RH) prior to implantation and to the performance data with the cochlear implant after 1 year. There was overall a decreased level of expression of BDNF-regulated proteins in profoundly hearing-impaired patients compared to patients with some RH. Phospholipid transfer protein was positively correlated to the preoperative hearing level of the patients. Our data show that combination of gene expression arrays and bioinformatic analysis can aid in the prediction of downstream signaling proteins related to the BDNF pathway. Proteomic analysis of perilymph may help to identify the presence or absence of these molecules in the diseased organ. The impact of such prediction algorithms on diagnosis and treatment needs to be established in further studies.
人工耳蜗植入的结果取决于多个变量，包括耳蜗的基础健康状况。在动物模型中，脑源性神经营养因子（BDNF）已被证明可支持螺旋神经节神经元并改善植入功能。内源性BDNF或BDNF调节的蛋白质是否可用作预测耳蜗健康和植入结果的生物标志物尚未得到研究。在颅底手术期间，从听力正常的患者（n = 3）获取的人耳蜗组织中鉴定出BDNF和下游信号分子的基因表达。基于基因表达数据，利用生物信息学分析来预测BDNF对蛋白质的调节作用。通过纳米级液相色谱-串联质谱法（nano LC-MS/MS），在人工耳蜗植入期间或因切除前庭神经鞘瘤而进行颅底手术时，从听力受损患者（n = 38）获取的外淋巴（n = 41）中研究了与这些基因相对应的蛋白质的存在情况。尽管有三名患者接受了双侧人工耳蜗植入，但仍对41份外淋巴样本进行了质谱分析。在任何外淋巴样本中均未检测到这些特定的BDNF调节蛋白。随后，使用 Ingenuity Pathway Analysis（IPA）对外淋巴蛋白质组数据进行靶向分析，确定了人外淋巴中可能受BDNF调节的其他蛋白质。这些BDNF调节的蛋白质与植入前残余听力（RH）的存在以及人工耳蜗植入1年后的性能数据相关。与有一些RH的患者相比，极重度听力受损患者中BDNF调节蛋白的表达水平总体上有所降低。磷脂转移蛋白与患者的术前听力水平呈正相关。我们的数据表明，基因表达阵列和生物信息学分析相结合有助于预测与BDNF途径相关的下游信号蛋白。外淋巴的蛋白质组分析可能有助于确定患病器官中这些分子的存在与否。这种预测算法对诊断和治疗的影响需要在进一步的研究中确定。
