Ear Level Cooling for Otoprotection

耳部冷却以保护耳部

• 批准号: 10570988
• 负责人: Christopher Spankovich
• 金额: $ 19.38万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570988
• 关键词: Acute; Alternative Therapies; Aluminum; Animal Model; Animals; Antibodies; Apoptotic; Audiology; Auditory; BODIPY; Binding Proteins; 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; Operative Surgical Procedures; Pathology; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Platinum; Predisposition; Prevention; Protein Binding Domain; RNA Binding; RNA-Binding Proteins; 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; 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; pharmacologic; prevent; protective effect; response; tool; translational potential; 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.

摘要 我们先前使用冷水耳证明了对顺铂引起的听力损失有显著的保护作用。 运河灌溉。然而，这项研究仅限于单次注射顺铂和急性时间段。 (斯潘科维奇等人)2016)。最近，我们研究了耳道局部降温的应用。 重复剂量的顺铂，在一段延长的时间内，并使用替代的冷却方法(EAR 由Peltier装置冷却的酒吧)。在这里，我们建议将我们的局部耳部降温的新应用推广到 减轻药物引起的听力损失；我们称之为凉耳保护耳腔(Cool)疗法。 假设：我们假设(1)我们的冷疗方法在大鼠模型中显示出保护作用；(2)保护作用 我们的冷疗是通过降低耳蜗对顺铂的摄取、表达或冷休克来实现的 蛋白质，减少上下游细胞凋亡的细胞死亡途径；(3)我们将观察到 通过我们的冷疗保护前庭免受损伤。 具体目标：目标1.确定冷疗是否降低顺铂摄取和听觉前庭 病理，增加编码冷休克蛋白的转录本的表达，并减少细胞 压力途径。 研究设计：对于AIM 1，豚鼠和Long Evans大鼠在接受顺铂治疗的同时， 冷疗，与假对照和温热动物相比。目标1(A)将决定我们的调查结果 移植到另一个物种(大鼠)，探索前庭效应。目标1(B)将检测抗体 顺铂DNA加合物免疫染色、质谱法测定耳蜗铂浓度 组织，以及用荧光标记顺铂治疗的动物的共聚焦图像。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。