Iduna通过拮抗Parthanatos防治噪声性聋

Previous studies have shown that cell apoptosis is a key for noise-induced hearing loss. We have performed anti-apoptotic protection study, and found that XIAP overexpression can decrease the apoptosis caused by noise exposure. However, the protective effect is discrepancy with our expectations. One of the possible reasons is that the XIAP plays the role of anti-apoptotic by directed inhibition of the Caspase. Therefore, if cell death does not depend on Caspase, XIAP will not be able to play its protective role. Parthanatos is a recently discovered form of cell death without Caspase participation. In preliminary experiments, we found the Parthanatos involved in cochlear cell death after noise exposure. The Iduna is a recently discovered neuroprotective protein and has the powerful role against Parthanatos.This project is proposed on the basis of our preliminary studies, to confirm the Parthanatos involved in noise-induced cochlear cell death and its activation pathway, explore the the protection of Iduna against Parthanatos carried by surface-exposed tyrosine residues knockout AAV2 via cochlear local transfection and its protection mechanisms.

既往研究证明噪声暴露后的耳蜗细胞凋亡是噪声性聋发生的关键环节。我们前期开展了抗凋亡保护耳蜗细胞的研究，发现XIAP可以遏制噪声暴露导致的细胞凋亡。然而，其对听力的保护作用与我们的预期有一定差距。可能原因为噪声暴露后耳蜗细胞存在不依赖于Caspase的死亡方式，因而，XIAP无从发挥其保护作用。Parthanatos是最近发现的一种死亡形式，其发生过程无需Caspase的参与。预实验中，项目组初步证实Parthanatos 参与噪声暴露后耳蜗细胞的死亡。Iduna是新发现的神经保护蛋白，具有强大的拮抗Parthanatos的作用。本项目拟在前期研究及预实验的基础上，确证Parthanatos参与噪声导致的耳蜗细胞的死亡及其激活通路；探索采用项目组前期制备的表面酪氨酸残基敲除的AAV2载体携带Iduna的耳蜗局部转染拮抗Parthanatos，从而保护噪声暴露导致的耳蜗细胞死亡的可能性及机制。

既往研究证明噪声暴露后的耳蜗细胞凋亡是噪声性聋发生的关键环节。我们前期开展了抗凋亡保护耳蜗细胞的研究，发现XIAP可以遏制噪声暴露导致的细胞凋亡。然而，其对听力的保护作用与我们的预期有一定差距。可能原因为噪声暴露后耳蜗细胞存在不依赖于Caspase的死亡方式，因而，XIAP无从发挥其保护作用。Parthanatos是最近发现的一种死亡形式，其发生过程无需Caspase的参与。本项组项目证实Parthanatos参与了噪声导致的耳蜗细胞的死亡，PAR大量合成及AIF细胞核转位是噪声暴露后耳蜗细胞Parthanatos发生的关键信号分子，采用项目组前期制备的表面酪氨酸残基敲除的AAV2载体携带Iduna的耳蜗局部转染拮抗Parthanatos，发现Iduna具有强大的保护耳蜗细胞的功能。其通过与PAR结合从而阻止AIF进入细胞核拮抗噪声暴露导致的Parthanatos发生，起到保护耳蜗细胞的作用。本项目的研究结果为噪声性聋的防治提供了新的思路。