Thiamine Deficiency and Acquired Auditory Neuropathy

硫胺素缺乏和获得性听觉神经病

• 批准号: 8484819
• 负责人: M. Charles Liberman
• 金额: $ 19.42万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484819
• 关键词: Acoustic Nerve; Acquired Deafness; Adult; Age; Animal Model; Animals; Antineoplastic Agents; Attenuated; Auditory; Auditory Brainstem Responses; Autopsy; Blood; Cancer Patient; Carboplatin; Cells; Child; Chinchilla (genus); Clinical Trials; Cochlea; Dependence; Development; Diet; Disease; Employee Strikes; Genes; Hair Cells; Hearing; Histopathology; Human; Image; Immunohistochemistry; Infant; Inherited; Inner Hair Cells; Institutes; Laboratories; Labyrinth; Lead; Life; Link; Low Birth Weight Infant; Mediating; Megaloblastic Anemia; Metabolism; Modeling; Mothers; Mus; Mutation; Neonatal; Neonatal Intensive Care Units; Neurons; Neuropathy; Newborn Infant; Nutritional status; Outer Hair Cells; Pathology; Pharmaceutical Preparations; Phenotype; Platinum; Population; Pregnancy; Premature Infant; Prevalence; Prevention; Reporter; Reporting; Rest; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Sensorineural Hearing Loss; Sensory; Sulfur; Supplementation; Symptoms; Synapses; Temporal bone structure; Testing; Thiamine; Thiamine Deficiency; Time; Water-Soluble Vitamin; Wernicke Encephalopathy; Work; base; cancer therapy; chemotherapy; deafness; feeding; hearing impairment; in utero; middle ear; mutant; novel; otoacoustic emission; ototoxicity; premature; research study; response

DESCRIPTION (provided by applicant): Auditory neuropathy (AN) is a type of deafness characterized by absence of auditory brainstem responses despite robust otoacoustic emissions, suggesting that outer hair cells are intact while inner hair cells (IHCs) and/or afferen neurons are dysfunctional. The AN phenotype can be either hereditary or acquired. Prematurity is an important risk factor for acquired AN in human populations, and, in animal models, AN can also be produced by the ototoxic anti-cancer drug, carboplatin. Two recent observations from our laboratory suggest that thiamine deficiency may be a key to the genesis of selective IHC loss, and therefore to acquired AN, in both prematurity and carboplatin therapy: 1) there is a striking prevalence of selective IHC loss in premature infants, and 2) IHCs have a unique vulnerability to thiamine (vitamin B1) deficiency in a mouse lacking a key transporter gene. Using animal models and human temporal bones obtained at autopsy, we will test the following hypotheses: 1) that the unique vulnerability of neonatal IHCs arises because of late-onset of expression of the key thiamine transporter genes in the inner ear, 2) that thiamine deficiency during late gestation or early post-natal life can cause selective IHC loss in otherwise healthy mice, and 3) that thiamine supplementation during carboplatin treatment can rescue the IHC loss that produces AN. If these novel hypothesized links are validated, simple therapies based on thiamine supplementation could be safe and effective in reducing the prevalence of hearing loss among infants in the neonatal intensive care unit and among children or adults undergoing anti-cancer therapies with platinum-based drugs.

描述（由申请人提供）：听觉神经病（AN）是一种耳聋，其特征是尽管耳声发射强劲，但缺乏听觉脑干反应，表明外毛细胞完整，而内毛细胞（IHC）和/或传入神经元功能障碍。 AN 表型可以是遗传性的，也可以是获得性的。早产是人类获得性 AN 的重要危险因素，在动物模型中，耳毒性抗癌药物卡铂也可以产生 AN。我们实验室最近的两项观察结果表明，在早产儿和卡铂治疗中，硫胺素缺乏可能是选择性 IHC 丢失的关键，从而导致获得性 AN：1) 早产儿选择性 IHC 丢失的发生率惊人，2) 在缺乏关键转运蛋白基因的小鼠中，IHC 对硫胺素（维生素 B1）缺乏具有独特的脆弱性。使用尸检中获得的动物模型和人类颞骨，我们将测试以下假设：1）新生儿 IHC 的独特脆弱性是由于内耳中关键硫胺素转运蛋白基因的晚发表达而产生的，2）妊娠晚期或产后早期的硫胺素缺乏可能导致其他健康小鼠的选择性 IHC 损失，3） 卡铂治疗可以挽救产生 AN 的 IHC 损失。 如果这些新的假设联系得到验证，基于硫胺素补充的简单疗法可能安全有效地降低新生儿重症监护病房的婴儿以及接受铂类药物抗癌治疗的儿童或成人的听力损失患病率。