Does strial microischemia enhance cochlear aminoglycoside ototoxicity

描述（由申请人提供）：声学过度刺激或高血压调节耳蜗血流，导致血管纹暂时和可逆的微缺血。心肌微缺血的特征在于血管直径的不规则性和高渗透性，即微渗漏。单独的耳蜗缺血可引起突发性听力损失和耳鸣。微渗漏和全身应用氨基糖苷类抗生素联合应用可加重氨基糖苷类抗生素的代谢，并推测其耳毒性。本研究拟探讨声暴露、高血压、年龄等因素对耳微渗漏的影响，建立可靠的耳毒性小鼠模型。本项目的具体目标是：目标1：验证噪声诱导的微渗漏小鼠模型。我们将确定可靠地诱导微渗漏的声刺激条件（例如，单剂量，间断声暴露）。目的2：通过增加CBA/CaJ小鼠的血容量，确定高血压或年龄在诱导血管微渗漏中的作用。此外，我们将研究年龄对C57 BL/6小鼠（一种早发性年龄相关性听力损失的品系）耳蜗微渗漏的影响。目的3：确定血管活性剂是否能预防血管微渗漏。我们将使用血管扩张剂或血管收缩剂来调节动脉血流量，并确定它们是否减少微渗漏。该项目的成果将建立可靠的星状微渗漏小鼠模型。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，例如高血压或血液流动不良。此外，我们寻求确定潜在的干预措施，以尽量减少脑微缺血，并降低耳毒性的风险。

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.