Drug manipulation of noise-induced hearing loss

描述(申请人提供)：本研究的长期目标是 开发药物，以减少强烈的声音对耳蜗的影响。 我们实验室最近的结果表明，三磷酸腺苷拮抗剂PPADS， 减少强烈的声音对耳蜗的影响，如监测 失真产物耳声发射(DPOAE)。我们的工作假设是 PPADS阻断内源性ATP作用于受体的影响 Deiters细胞的外淋巴表面。外源应用的三磷酸腺苷去极化 并增加细胞内的游离钙水平。Deiters‘s 细胞似乎由第II类传入神经的分支支配。 外毛细胞(OHC)。这表明作用于ATP的ATP的来源 Deiters细胞上的受体可能是这些神经纤维的终末。 从解剖学上讲，Deiters细胞附着在毛细胞的底部和顶端， 基底膜和网状板。因此，Deiters的细胞可以扮演一个 在细胞转导过程中的重要作用 立体纤毛。Deiters的细胞可以通过改变自身的硬度来做到这一点。这个 有待检验的假设是，作为一种神经递质被提出的ATP 耳蜗，与Deiters细胞上的受体反应，以增强有害的 强音对耳蜗的影响。这一假设将通过以下方式检验 实验：(1)确定内源性三磷酸腺苷是否增强有害物质 强声作用下检测ATP激动剂和拮抗剂对强声的影响 声音暴露；(2)确定ATP的作用机制是否涉及 Deiters细胞的移动或刚度变化；以及(3)确定 Deiters细胞上的受体机制涉及代谢型P2Y型 受体。

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop drugs that will decrease the effects of intense sound on the cochlea. Recent results from our laboratory have shown that PPADS, an ATP antagonist, decreases the effect of intense sound on the cochlea as monitored with distortion product otoacoustic emissions (DPOAEs). Our working hypothesis is that PPADS is blocking the effects of endogenous ATP acting on receptors on the perilymph surface of Deiters' cells. Exogenously applied ATP depolarizes Deiters' cells and increases their intracellular free calcium levels. Deiters' cells are innervated by what appears to be branches of type II afferents to the outer hair cells (OHCs). This suggests that the source of the ATP acting on ATP receptors on the Deiters' cells may be the terminals of these nerve fibers. Anatomically, Deiters' cells are attached to the base and apex of OHCs, to the basilar membrane, and reticular lamina. Thus Deiters' cells may play a significant role in the transduction process carried out by the OHCs and their stereocilia. Deiters' cells may do this by altering their own stiffness. The hypothesis to be tested is that ATP, proposed as a neurotransmitter in the cochlea, reacts with receptors on the Deiters' cells to enhance the deleterious effects of intense sound on the cochlea. This hypothesis will be tested by experiments that: (1) determine if endogenous ATP enhances the deleterious effects of intense sound by testing ATP agonists and antagonists during intense sound exposure; (2) determine if the mechanism of action of ATP involves a movement of Deiters' cell or a stiffness change; and (3) determine if the receptor mechanism on Deiters' cells involves the metabotropic P2Y type of receptor.