Thiamine Deficiency and Acquired Auditory Neuropathy

描述（由申请人提供）：听神经病变（AN）是一种耳聋，其特征是尽管有强大的耳声发射，但缺乏听性脑干反应，这表明外毛细胞完好无损，而内毛细胞（IHCs）和/或后视神经元功能失调。AN表型既可以遗传也可以获得。早产是人类获得性an的一个重要危险因素，在动物模型中，an也可以由耳毒性抗癌药物卡铂产生。我们实验室最近的两个观察结果表明，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，因此是获得性AN的关键：1)早产儿中选择性IHC丢失的发生率惊人；2)缺乏关键转运基因的小鼠中，IHC对硫胺素（维生素B1）缺乏具有独特的脆弱性。利用动物模型和尸检获得的人类颞骨，我们将验证以下假设：1)新生儿IHC的独特脆弱性是由于内耳中关键硫胺素转运体基因的迟发性表达引起的；2)妊娠晚期或产后早期的硫胺素缺乏可导致其他健康小鼠的选择性IHC丢失；3)在卡铂治疗期间补充硫胺素可以挽救产生AN的IHC丢失。如果这些新的假设联系得到证实，那么以补充硫胺素为基础的简单疗法可以安全有效地降低新生儿重症监护病房的婴儿以及接受含铂类药物抗癌治疗的儿童或成人的听力损失发生率。

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. PUBLIC HEALTH RELEVANCE: Recent work has generated the novel hypothesis that a particular type of acquired deafness known as auditory neuropathy arises from the special dependence of one type of inner ear sensory cell, the inner hair cell, on thiamine, also known as vitamin B1. If the experiments proposed here to test this hypothesis are successful, the results should lead to a clinical trial of the efficacy of thiamine supplementation in the prevention of auditory neuropathy among newborns.