Cochlear trafficking and hair cell uptake of aminoglycosides

氨基糖苷类药物的耳蜗运输和毛细胞摄取

• 批准号: 8411596
• 负责人: Peter Stephen Steyger
• 金额: $ 43.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8411596
• 关键词: Acute; Acute Kidney Failure; Adverse effects; Affect; Agonist; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Apical; Auditory; Auditory Brainstem Responses; Bathing; Bioterrorism; Blast Injuries; Blood; Blood Vessels; Burn injury; Caliber; Cations; Cavia; Cell Death; Cell Line; Cells; Cellular Stress; Clinical; Cochlea; Cochlear duct; Data; Diabetes Mellitus; Endolymph; Endothelial Cells; Epithelial Cells; Epithelium; Gentamicins; Glucose Transporter; Goals; Hair; Hair Cells; Immunofluorescence Immunologic; Individual; Infant; Infusion Technique; Kanamycin; Knockout Mice; Labyrinth; Life; Liquid substance; Membrane; Modification; Molecular; Morphology; Mus; Perfusion; Perilymph; Phase III Clinical Trials; Play; Premature Infant; Prophylactic treatment; Proximal Kidney Tubules; Research; Route; Scala Tympani; Sensory; Sensory Hair; Sepsis; Sodium; Stress; Stria Vascularis; Surface; TRPA1 Channel; TRPV1 gene; Techniques; Testing; Texas red; Tight Junctions; Toxic effect; Translating; Zebrafish; aminoglycoside-induced ototoxicity; bactericide; basolateral membrane; cellular transduction; clinically relevant; combat; deafness; equilibration disorder; fluorophore; hearing impairment; in vivo; inhibitor/antagonist; macromolecule; nephrotoxicity; neuromast; ototoxicity; prevent; therapeutic effectiveness; trafficking; uptake

DESCRIPTION (provided by applicant): Aminoglycoside antibiotics are essential for treating life-threatening bacterial sepsis, yet induce acute nephrotoxicity and permanent deafness/balance disorders. These noxious side-effects affect as many as 120,000 individuals each year in the US, particularly infants and premature babies. The long-term goal of this research is to prevent the cochlear uptake of aminoglycosides and subsequent ototoxicity, thus preserving life-long auditory function. Aminoglycosides like gentamicin cross the cochlear blood-labyrinth barrier into the cochlear fluids and enter sensory hair cells, inducing toxicity and hearing loss. Our recent data suggest that systemically-delivered gentamicin is trafficked from the strial vasculature, across the stria vascularis, into endolymph prior to hair-cell uptake. We have identified a candidate aminoglycoside transporter. Pharmacological inhibition of this transporter reduces cochlear, strial and hair-cell uptake of gentamicin. The specific aims of this project are: "First, to determine if other aminoglycosides are predominantly trafficked to cochlear hair cells via the stria vascularis and endolymph in vivo (Aim 1)." Second, to test whether inhibitors of aminoglycoside trafficking preserves auditory function by preventing hair cell toxicity, and maintain the bactericidal efficacy of aminoglycosides. We will also determine if deletion of the candidate aminoglycoside transporter ameliorates aminoglycoside ototoxicity (Aim 2). "And, third, investigate whether structural modification of aminoglycosides prevents cochlear trafficking, hair cell uptake and hair cell toxicity (Aim 3). Identifying the routes and molecular mechanisms of aminoglycoside trafficking across the BLB and into hair cells is crucial to develop new pharmacotherapeutic strategies that preserve auditory function during aminoglycoside therapy. Clinically-relevant inhibitors of aminoglycoside trafficking should not affect the bactericidal efficacy of aminoglycosides. Preventing cochlear trafficking and hair cell uptake of aminoglycosides will allow clinicians to use aminoglycosides more aggressively for treating life-threatening bacterial sepsis, specific agents of bioterrorism, and for prophylaxis in combat, severe burns and blast injuries.

说明(申请人提供)：氨基糖苷类抗生素对于治疗危及生命的细菌败血症是必不可少的，但会导致急性肾毒性和永久性耳聋/平衡障碍。在美国，这些有害的副作用每年影响多达12万人，特别是婴儿和早产儿。这项研究的长期目标是防止耳蜗胺糖苷类药物的摄取和随后的耳毒性，从而保护终身听觉功能。像庆大霉素这样的氨基糖苷类药物穿过耳蜗血迷路屏障进入耳蜗液，进入感觉毛细胞，导致毒性和听力损失。我们最近的数据表明，系统输送的庆大霉素在毛细胞摄取之前从血管纹通过血管纹进入内淋巴。我们已经确定了一个候选的氨基糖苷类转运体。这种转运蛋白的药理抑制减少了耳蜗部、产业部和毛细胞对庆大霉素的摄取。该项目的具体目标是：“首先，确定其他氨基糖苷类化合物是否主要通过体内的血管纹和内淋巴转运到耳蜗毛细胞(目标1)。”第二，测试氨基糖苷转运的抑制剂是否通过防止毛细胞毒性来保护听觉功能，并保持氨基糖苷类药物的杀菌效果。我们还将确定候选氨基糖苷转运体的缺失是否可以改善氨基糖苷类耳毒性(目标2)。“第三，研究氨基糖苷类药物的结构修饰是否能阻止耳蜗性转运、毛细胞摄取和毛细胞毒性(目标3)。确定氨基糖苷类药物转运的途径和分子机制对于开发新的药物治疗策略，在氨基糖苷类药物治疗期间保护听觉功能至关重要。临床相关的氨基糖苷类转运抑制剂不应影响氨基糖苷类药物的杀菌效果。阻止氨基糖苷类化合物的耳蜗性转运和毛细胞摄取将使临床医生能够更积极地使用氨基糖苷类抗生素来治疗危及生命的细菌败血症、生物恐怖主义的特定制剂，以及用于战斗、严重烧伤和爆炸伤的预防。