Molecular Mechanisms of Aminoglycoside Ototoxicity

项目概要 氨基糖苷类药物广泛用于治疗严重感染，因为它们对许多多重感染具有良好的活性。 耐药革兰氏阴性菌。然而，它们强烈且不可逆的耳毒性极大地限制了 他们的临床用途。本研究的总体目标是调查潜在的病理机制 AG 耳毒性并提供新的治疗靶点来预防它。我们建议研究以下功能 毛细胞中的氨基糖苷结合蛋白，即内耳的感觉受体。在我们的初步研究中， 我们已经鉴定出几种对氨基糖苷类耳毒性至关重要的蛋白质。根据我们的初步数据，我们 假设氨基糖苷类耳毒性涉及一种新的病理机制。来测试我们的 假设，我们将： i) 继续研究这些蛋白质在头发中的表达、定位和功能 细胞； ii) 继续鉴定携带这些基因突变的小鼠品系； iii) 继续调查 这些蛋白质在氨基糖苷类耳毒性中的功能相互作用。我们的初步数据显示了可行性 我们的方法。我们预计我们的研究将为分子机制提供新的见解 潜在的氨基糖苷类耳毒性，并为开发新方法提供新线索 预防氨基糖甙类药物引起的听力损失。

PROJECT SUMMARY Aminoglycosides are widely used to treat serious infections, as they have good activity against many multi- drug resistant Gram-negative organisms. However, their strong and irreversible ototoxicity significantly limits their clinical usage. The overall goal of this research is to investigate the pathological mechanisms underlying AG ototoxicity and provide novel therapeutic targets to prevent it. We propose to investigate the functions of aminoglycoside-binding proteins in hair cells, the sensory receptors in the inner ear. In our preliminary studies, we have identified several proteins essential for aminoglycoside ototoxicity. Based on our preliminary data, we hypothesize that a novel pathological mechanism is involved in aminoglycoside ototoxicity. To test our hypothesis, we will: i) continue to investigate the expression, localization and functions of these proteins in hair cells; ii) continue to characterize mouse lines carrying mutations in these genes; iii) continue to investigate the functional interactions of these proteins in aminoglycoside ototoxicity. Our preliminary data show the feasibility of our approach. We anticipate that our studies will shed new insights into the molecular mechanisms underlying aminoglycoside ototoxicity and provide new leads for the development of new approaches to prevent aminoglycoside-induced hearing loss.