Does strial microischemia enhance cochlear aminoglycoside ototoxicity

心房微缺血是否会增强耳蜗氨基糖苷类耳毒性

• 批准号: 8103768
• 负责人: Hongzhe Li
• 金额: $ 15.4万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8103768
• 关键词: Acoustic Stimulation; Acoustics; Acute; Age; Aminoglycoside Antibiotics; Aminoglycosides; Angiotensin II; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Blood Volume; Blood capillaries; Blood flow; Body Weight; Brain; Brain Hypoxia-Ischemia; C57BL/6 Mouse; CBA/CaJ Mouse; Caliber; Cochlea; Confocal Microscopy; Data; Diet; Disodium Salt Nitroprusside; Dose; Endothelin-1; Event; Extravasation; Gentamicins; Hearing; Heart; Heart Rate; Histamine; Hour; Hydralazine; Hypertension; Infarction; Injection of therapeutic agent; Intervention; Ischemia; Kidney; Labyrinth; Life Style; Magnetic Resonance Imaging; Metabolic; Modeling; Monitor; Mus; Noise; Organ; Outcome; Pathology; Permeability; Pharmaceutical Preparations; Physiologic pulse; Physiological; Population; Presbycusis; Reagent; Reporting; Research; Risk; Risk Factors; Saline; Stria Vascularis; Tail; Testing; Texas red; Tinnitus; Tissues; Topical application; Toxic effect; Vascular Permeabilities; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Veins; age effect; aged; aminoglycoside-induced ototoxicity; capillary; capillary bed; early onset; efficacy testing; experience; hearing impairment; intravenous injection; local drug delivery; mouse model; ototoxicity; prevent; research study; sedentary; sound; trafficking; uptake

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.

描述（由申请人提供）：声音过度刺激或高血压调节耳蜗血流，导致血管纹中暂时且可逆的微缺血。心房微缺血的特征是血管直径不规则和渗透性升高，即心房微渗漏。仅耳蜗缺血就可能导致突然的听力丧失和耳鸣。心房微渗漏和氨基糖苷类抗生素的全身给药相结合可以加剧氨基糖苷类抗生素的心房运输，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）可以诱发心房微渗漏，并建立可靠的耳毒性小鼠模型。该项目的具体目标是： 目标 1：验证噪声诱导的心房微渗漏小鼠模型。我们将确定可靠地引起心房微渗漏的声刺激条件（例如，单剂量、中断的声音暴露）。目标 2：通过增加 CBA/CaJ 小鼠的血容量来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 小鼠心房微渗漏的影响，C57BL/6 小鼠是一种早期出现与年龄相关的听力损失的品系。目标 3：确定血管活性试剂是否可以防止心房微渗漏。我们将使用血管扩张剂或血管收缩剂来调节心房血流并确定它们是否减少微渗漏。该项目的成果将建立一个可靠的心房微渗漏小鼠模型。这很重要，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，以在药理学上最大限度地减少心房微缺血，并降低耳毒性的风险。 公众健康相关性：声音过度刺激或高血压会调节耳蜗血流，导致血管纹出现暂时性、可逆性微缺血。耳蜗微缺血和氨基糖苷类抗生素的全身给药相结合可以加剧氨基糖苷类抗生素在心房内的运输，从而加剧其耳毒性。拟议的研究将确定纹状体微缺血的几个危险因素，并建立可靠的耳毒性小鼠模型。