心房钠尿肽及其受体对噪声性听力损伤保护作用及其机制的研究

Noise-induced hearing loss (NIHL) is a major health problem in the modern society. Damage of cochlear hair cells (HCs) primarily resulting from noise trauma, or degeneration of spiral ganglion neurons (SGNs) secondarily occurring as a result of hair cells loss, ultimately leads to permanent sensorineural hearing loss after NIHL. Because spontaneous regeneration of mammalian HCs and SGNs does not take place, cell-protective therapies for both HCs and SGNs are profoundly needed to prevent NIHL. Research showed that inhibitors of cyclic guanosine monophosphate (cGMP)-hydrolyzing phosphodiesterase 5 (Pde5) prevented hearing dysfunction and death of HCs and SGNs after noise expouse, suggesting an endogenous protective cGMP–cGMP-dependent protein kinases (PKG) signaling pathway facilitates protective processes in NIHL, and cGMP-signaling related drugs as possible candidates for the treatment of NIHL. Specially, the synthesis of the intracellular second messenger cGMP can be catalyzed by the interaction of the particulate guanylyl cyclase-coupled natriuretic peptide receptor-A (NPR-A) with its ligand, atrial natriuretic peptide (ANP). In the previous study, we have previously provided direct evidence for the presence of ANP and its receptors (NPR-A and natriuretic peptide receptor-C, NPR-C) in the spiral ganglion and the organ of Corti, the sensory and neuronal region of the cochlea, suggesting possible protective effects for ANP and its receptors aganist NIHL. In this study, we aim to identify the cellular localizations and expression levels of ANP and its receptors in the organ of Corti, their potential actions in modulating functions of HCs, and their protective roles aganist damage and degeneration of HCs and SGNs in NIHL. Overall, our study will represent an alternative approach for developing new and effective therapies for hearing impairment and sensorineural hearing loss.

噪声性听力损伤（NIHL）是现代社会的一大健康问题，其引发耳蜗毛细胞（HCs）和螺旋神经元（SGNs）损伤，最终导致永久性听力损伤。由于哺乳动物HCs和SGNs均不可再生，如何防护噪声性HCs、SGNs损伤成为NIHL防治的关键。研究证实环磷酸鸟苷（cGMP）水解酶（磷酸二酯酶5）抑制剂可减轻NIHL，提示cGMP–蛋白激酶PKG信号通路具有NIHL保护效应，cGMP信号通路相关分子可作为NIHL防治的新靶点。cGMP的合成可通过心房钠尿肽（ANP）和钠尿肽A型受体介导。我们前期研究证实ANP及其受体在大鼠螺旋神经节、螺旋器等耳蜗神经感觉区域均具有表达，提示其可能具有潜在的NIHL保护效应。本项目通过研究ANP及其受体在耳蜗螺旋器的细胞定位及合成、表达，对毛细胞生理功能的调节作用，及其对噪声暴露条件下HCs和SGNs损伤的保护作用及其可能机制，为NIHL的防治提供新的理论依据。

噪声性听力损伤（NIHL）是现代社会的一大健康问题，其防治的关键在于减轻和保护噪声引发的耳蜗毛细胞（HCs）和螺旋神经元（SGNs）损伤，阻止永久性听力损伤的发生。研究证实环磷酸鸟苷（cGMP）水解酶抑制剂可减轻NIHL，提示cGMP信号通路相关分子具有NIHL保护效应，可作为NIHL防治的新靶点。cGMP的合成可通过心房钠尿肽（ANP）和钠尿肽A型受体介导。在前期研究中，我们证实ANP及其受体在大鼠螺旋神经节、螺旋器等耳蜗神经感觉区域均具有表达，提示其可能具有潜在的NIHL保护效应。本项目研究ANP及其受体（NPR-A和NPR-C）在大鼠耳蜗螺旋器的细胞定位及合成、表达，对毛细胞生理功能的调节作用，及其对噪声暴露条件下HCs和SGNs损伤的保护作用。研究证实了ANP在螺旋器内、外毛细胞以及部分支持细胞胞质中具有表达，NPR-A和NPR-C在螺旋器内、外毛细胞基底外侧区表达,耳蜗螺旋器ANP及其受体mRNA和蛋白表达量随着出生后发育发生变化；ANP及NPR-A受体通过抑制内毛细胞内向钙电流、增强外向钾电流水平，降低膜电位振荡频率，提高膜振荡的激活电流水平，降低毛细胞兴奋性，可能参与毛细胞–螺旋神经元突触传递功能和听觉转导的调节；ANP药物治疗能减轻噪声暴露引起的耳蜗形态和听功能损伤，表现为ANP治疗组大鼠听性脑干反应（ABR）和畸变产物耳声发射（DPOAE）阈移，螺旋神经节与螺旋器内、外毛细胞形态损伤、缺失的程度较噪声暴露组均有明显减轻。本研究为NIHL的防治提供新依据，未来有望为NIHL和感音神经性聋的药物防治带来新的曙光。