Does strial microischemia enhance cochlear aminoglycoside ototoxicity

描述(申请人提供)：声学过度刺激或高血压调节耳蜗血流量，在血管纹处引起暂时性和可逆性微缺血。工业微缺血以血管内径不规则、通透性增高为特征，即工业微渗漏。单纯的耳蜗性缺血可能会导致突发性听力损失和耳鸣。氨基糖苷类抗生素的工业微渗漏和全身给药可加剧氨基糖苷类药物的工业转运，并推测其耳毒性。在本方案中，我们将确定哪些危险因素，包括噪声暴露、高血压或年龄，可以诱发工业微渗漏，并建立可靠的耳毒性小鼠模型。本项目的具体目标是：目标1：验证噪声诱导的工业微渗漏小鼠模型。我们将确定可靠地导致STORE微泄漏的声刺激条件(例如，单次剂量、间断声暴露)。目的：通过增加CBA/CAJ小鼠的血容量，确定高血压或年龄对工业微渗漏的影响。此外，我们还将检测年龄对C57BL/6小鼠微渗漏的影响，C57BL/6是一种较早发生年龄相关性听力损失的品系。目的3：确定血管活性物质是否能防止微渗漏。我们将使用血管扩张剂或血管收缩药来调节血管血流，并确定它们是否减少微渗漏。本项目的研究成果将为工业微渗漏建立可靠的小鼠模型。这一点很重要，因为微缺血可能是增加耳毒性风险的几个因素的基础，例如高血压或血流不良。此外，我们寻求确定潜在的干预措施，以从药理上最大限度地减少微缺血，并降低耳毒性的风险。 公共卫生相关性：声学过度刺激或高血压调节耳蜗血流量，在血管纹处引起暂时性和可逆性微缺血。耳蜗微缺血和氨基糖苷类抗生素的全身应用可增加氨基糖苷类药物的产业内转运，从而导致其耳毒性。这项研究将确定工业微缺血的几个危险因素，并建立可靠的耳毒性小鼠模型。

DESCRIPTION (provided by applicant): Acoustic overstimulation or hypertension modulates cochlear blood flow, causing temporary and reversible microischemia in the stria vascularis. Strial microischemia is characterized by irregularity in vessel diameters and elevated permeability, i.e. strial micro-leakage. Cochlear ischemia alone may cause abrupt hearing loss and tinnitus. Combined strial micro-leakage and systemic administration of aminoglycoside antibiotics can escalate aminoglycoside strial trafficking, and presumptively its ototoxicity. In this proposal, we will determine which risk factors, including sound exposure, hypertension or age can induce strial micro-leakage, and establish a reliable ototoxic mouse model. The specific aims of this project are to: Aim 1: validate a noise-induced strial micro-leakage mouse model. We will determine the acoustic stimulation conditions that reliably induce strial micro-leakage (e.g., single dose, interrupted sound exposures). Aim 2: determine the effect of hypertension or age in inducing strial micro-leakage, by increasing blood volume in CBA/CaJ mice. In addition, we will examine effect of age on strial micro-leakage in C57BL/6 mice, a strain with early onset of age-related hearing loss. Aim 3: determine if vasoactive reagents prevent strial micro-leakage. We will use vasodilators or vasoconstrictors to regulate the strial blood flow and determine if they reduce micro-leakage. The outcome of this project will establish a reliable mouse model for strial micro-leakage. This is important as microischemia may underlie several factors that increase the risk of ototoxicity, such as hypertension or poor blood flow. In addition, we seek to identify potential interventions to pharmacologically minimize strial microischemia, and reduce the risk of ototoxicity. PUBLIC HEALTH RELEVANCE: Acoustic overstimulation or hypertension modulates cochlear blood flow, causing temporary and reversible microischemia in the stria vascularis. Combination of cochlear microischemia and systemic administration of aminoglycoside antibiotics can escalate aminoglycoside intra-strial trafficking, and consequently its ototoxicity. The proposed research will determine several risk factors on strial microischemia, and establish a reliable ototoxic mouse model.