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，引起血管纹暂时性和可逆性微缺血。纹状体微缺血的特征是血管直径不规则和通透性升高，即纹状体微渗漏。仅耳蜗缺血就可引起突发性听力丧失和耳鸣。联合试验微渗漏和全身给药氨基糖苷类抗生素可增加氨基糖苷类药物的试验贩运，并推测其耳毒性。在本提案中，我们将确定哪些危险因素，包括声音暴露，高血压或年龄，可以诱导耳蜗微渗漏，并建立可靠的耳毒性小鼠模型。本项目的具体目的是：目的1：验证噪声诱导的实验性微泄漏小鼠模型。我们将确定可靠地诱导试验微泄漏的声刺激条件（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，确定高血压或年龄对诱导心房微渗漏的影响。此外，我们将研究年龄对C57BL/6小鼠试验微漏的影响，C57BL/6是一种早发性年龄相关性听力损失的小鼠。目的3：确定血管活性试剂是否能防止毛细血管微渗漏。我们将使用血管扩张剂或血管收缩剂来调节试验血流量，并确定它们是否减少微渗漏。本课题的研究成果将建立可靠的小鼠肾微渗漏模型。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，如高血压或血流量不足。此外，我们寻求确定潜在的干预措施，以药理学上最小化试验微缺血，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.