cGMP survival signalling for prevention of hearing loss

用于预防听力损失的 cGMP 生存信号

• 批准号: 234442174
• 负责人: Professor Dr. Lukas Rüttiger
• 金额: --
• 依托单位: Tübinger Hörforschungszentrum
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/234442174?language=en
• 关键词: cGMP; survival; signalling; prevention; hearing

The potential capacity of cGMP activation for protection of sensory organs in the inner ear is not fully understood. Our previous findings suggested that the phosphodiesterase 5 inhibitor may provide protection against trauma-induced hearing loss and sensory hair cell death potentially by signalling via a common cGMP/cGMP-dependent protein kinase type I (cGKI) pathway in the inner ear. At the same time we have identified a higher vulnerability and a reduced recovery from noise-induced auditory injury in mouse mutants globally lacking cGKI. It is the overall aim of this project to elucidate the role of the cGMP generators and effectors involved in hair cell survival in the injured or challenged auditory system, and to monitor spatiotemporal cGMP dynamics during both sudden and progressive damage. In order to validate this pathway for early identification and treatment of hearing loss, we will monitor the auditory responses in the presence and absence of various cGMP elevating agents in different animal models. We have subjected membrane-bound guanylyl cyclase (GC-A/B) mutants and mice lacking subunits of the soluble NO-GC to a combination of physiological and molecular tests for spontaneous or induced auditory signal processing disorders. We found that GC-A mediates protection from noise-induced hearing loss, whereas NO-GC may have autonomous functions in inner and outer hair cells including changes in central brainstem adaptation and distinct efferent feedback control. Further studies need to dissect the individual functions of the NO-GC isoforms in sensory cells and central nuclei for spontaneous and trauma-induced hearing loss and their potential use as pharmacological targets in the development of auditory pathologies. We will further explore the molecular and cellular aspects of degeneration and regeneration during auditory injury, which should validate the therapeutic potential of GC-A and its ligands for the protection of the ear during auditory stress. GC-B deletion leads to failure of auditory nerve bifurcation in the auditory brainstem. We suggest that this may lead to a moderate hearing loss possibly linked to disturbed efferent feedback loops. Therefore also the role of GC-B/cGMP for the central inhibitory neuronal circuits in the cochlear nucleus complex and for damage-induced changes in binaural hearing, adaptation, and plasticity will be explored in detail. The functional experiments shall be corroborated by exploring the cGMP effector proteins downstream of the distinct cGMP generators and by directly visualizing cGMP in different cell types of the organ of corti under pathophysiological conditions using transgenic mice with inducible expression of a cGMP sensor specifically in different auditory cell types. Using comprehensive cellular, functional and perceptual assays we may decode the cGMP cascade in the ear and contribute to the general state of knowledge for cell protection and survival by cGMP and cGMP elevating compounds.

环鸟苷酸激活保护内耳感觉器官的潜在能力尚未完全了解。我们先前的研究结果表明，磷酸二酯酶5抑制剂可能通过内耳中常见的cGMP/cGMP依赖性蛋白激酶I型（cGKI）通路发出信号，从而保护损伤诱导的听力损失和感觉毛细胞死亡。与此同时，我们已经确定了一个更高的脆弱性和减少恢复噪音诱导的听觉损伤的小鼠突变体全球缺乏cGKI。本项目的总体目标是阐明cGMP发生器和效应器在受伤或受到挑战的听觉系统中参与毛细胞存活的作用，并在突然和进行性损伤期间监测时空cGMP动力学。为了验证这一途径对听力损失的早期识别和治疗，我们将在不同的动物模型中监测存在和不存在各种cGMP升高剂的听觉反应。我们进行了膜结合鸟苷酸环化酶（GC-A/B）突变体和小鼠缺乏亚单位的可溶性NO-GC的生理和分子测试的组合自发或诱导的听觉信号处理障碍。我们发现，GC-A介导的保护噪声引起的听力损失，而NO-GC可能有自主的功能，在内和外毛细胞，包括中枢脑干适应和不同的传出反馈控制的变化。进一步的研究需要解剖的感觉细胞和中枢神经核团的自发性和创伤性听力损失的NO-GC亚型的个人功能，其潜在的用途作为药理学目标的发展听觉病理。我们将进一步探索听觉损伤过程中退化和再生的分子和细胞方面，这将验证GC-A及其配体在听觉应激过程中保护耳朵的治疗潜力。GC-B基因缺失导致听神经在听性脑干分叉失败。我们认为，这可能会导致中度听力损失可能与干扰传出反馈回路。因此，还将详细探讨GC-B/cGMP对耳蜗核复合体中的中枢抑制性神经元回路以及双耳听力、适应性和可塑性中损伤诱导的变化的作用。功能实验应通过探索不同cGMP发生器下游的cGMP效应蛋白，并通过使用在不同听觉细胞类型中具有cGMP传感器的诱导表达的转基因小鼠，在病理生理条件下直接观察Corti器官的不同细胞类型中的cGMP来证实。使用全面的细胞、功能和感知分析，我们可以解码耳中的cGMP级联，并有助于了解cGMP和cGMP升高化合物对细胞保护和存活的一般知识。