Ear Level Cooling for Otoprotection

耳部冷却以保护耳部

• 批准号: 10433343
• 负责人: Christopher Spankovich
• 金额: $ 23.25万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433343
• 关键词: Acute; Alternative Therapies; Aluminum; Animal Model; Animals; Antibodies; Apoptotic; Audiology; Auditory; BODIPY; Black race; Bolus Infusion; CASP3 gene; Cavia; Cell Death; Cells; Cellular Stress; Cisplatin; Cochlea; Cochlear Implants; Cochlear duct; Code; Complementary therapies; Coupled; Devices; Dose; Ear; Engineering; Exposure to; External auditory canal; FDA approved; Fluorescence; Free Radicals; Functional disorder; Hair Cells; Heart Injuries; In Situ Hybridization; Individual; Inductively Coupled Plasma Mass Spectrometry; Injections; Injury to Kidney; Irrigation; Lipid Peroxidation; Lipids; Literature; Long-Evans Rats; Mass Spectrum Analysis; Measures; Mediating; Metabolic; Methods; Modeling; Molecular Biology; Nervous System Trauma; Neurons; Neurosciences; Noise; Pathology; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Platinum; Predisposition; Prevention; Protein Binding Domain; RNA Binding; RNA-Binding Proteins; Rat-1; Rattus; Regimen; Research; Research Design; Role; Sensorineural Hearing Loss; Series; Testing; Therapeutic; Thinking; Time; Tissue imaging; Tissues; Toxin; Transcript; Translating; Translations; Up-Regulation; Water; Work; animal imaging; base; cisplatin induced hearing loss; cisplatin-DNA adduct; clinical translation; cohort; cold shock protein; confocal imaging; experimental study; guinea pig model; hearing preservation; iatrogenic injury; model design; natural hypothermia; novel; otoprotectant; ototoxicity; prevent; protective effect; response; time use; tool; uptake

ABSTRACT We previously demonstrated significant protection from cisplatin induced hearing loss using cool water ear canal irrigation. However, the study was limited to a single bolus injection of cisplatin and acute time period (Spankovich et al. 2016). More recently, we examined application of localized cooling of the ear canal with repeated doses of cisplatin, over an expanded period of time, and using an alternative method of cooling (ear bar cooled by a Peltier device). Here, we propose to advance our novel application of localized ear cooling in mitigation of drug induced hearing loss; which we call Cool OtOprotective ear Lumen (COOL) therapy. Hypotheses: We hypothesize that (1) our COOL therapy will show protection in a rat model; (2) protection from our COOL therapy is mediated by reduced cochlear uptake of cisplatin, expression or cold shock proteins, and reduced upstream and downstream cell apoptotic cell death pathways; (3) that we will observe protection from vestibular damage with our COOL therapy. Specific Aims: Aim 1. To determine whether COOL therapy reduces cisplatin uptake and auditory-vestibular pathology, increases the expression of transcripts that code for cold-shock proteins, and reduced cellular stress pathways. Study Design: For Aim 1, Guinea pig and Long Evans rats will be exposed to cisplatin while undergoing COOL therapy and compared to sham controls and warmed animals. Aim 1(a) will determine if our findings translate to another species (rat) and explore vestibular effects. Aim 1(b) will examine antibody immunostaining for cisplatin DNA-adducts, mass spectrometry measured platinum concentrations in cochlear tissue, and confocal images of animals treated with fluorescent tagged cisplatin. Aim 1(c,d) will examine expression of cold shock proteins and evidence of lipid perioxidation and caspase-3 activation.

抽象的 我们之前证明了使用冷水耳对顺铂引起的听力损失有显着的保护作用 运河灌溉。然而，该研究仅限于单次推注顺铂和急性时间段 （斯潘科维奇等人，2016）。最近，我们研究了耳道局部冷却的应用 在延长的时间内重复服用顺铂，并使用替代冷却方法（耳 由珀耳帖装置冷却的棒）。在这里，我们建议推进局部耳部冷却的新应用 减轻药物引起的听力损失；我们称之为冷耳保护耳腔 (COOL) 疗法。 假设：我们假设 (1) 我们的 COOL 疗法将在大鼠模型中显示出保护作用； (2)保护 我们的 COOL 疗法是通过减少耳蜗对顺铂的摄取、表达或冷休克来介导的 蛋白质，并减少上游和下游细胞凋亡的细胞死亡途径； （3）我们将观察到的 我们的 COOL 疗法可防止前庭损伤。 具体目标： 目标 1. 确定 COOL 疗法是否会降低顺铂摄取和听觉前庭功能 病理学，增加编码冷休克蛋白的转录物的表达，并减少细胞 压力途径。 研究设计：对于目标 1，豚鼠和 Long Evans 大鼠将在接受顺铂治疗时接触顺铂 冷疗法并与假对照组和温暖的动物进行比较。目标 1(a) 将确定我们的发现是否 转化为另一个物种（大鼠）并探索前庭效应。目标 1(b) 将检查抗体 顺铂 DNA 加合物的免疫染色，质谱法测量耳蜗中的铂浓度 用荧光标记的顺铂处理的动物的组织和共焦图像。目标 1(c,d) 将检查 冷休克蛋白的表达以及脂质过氧化和 caspase-3 激活的证据。