Basic Mechanisms in Hearing Loss of Cochlear Origin

描述（由申请人提供）： 目的：感音神经性听力损失（SNHL）与包括爆炸伤在内的军事服务的许多方面密切相关。该提案的目标是改善退伍军人SNHL的预防和治疗。 研究设计：为了提高我们对毛细胞（HC）损伤和损失的细胞过程的理解，将通过测定其表达和评估基因敲除小鼠中的HC损失来评估已知HC损伤和存活途径中分子亚型的贡献。为了改善SNHL预防，还将确定可以保护耳蜗HC免受损伤的药剂。为了改善SNHL的治疗，将鉴定增强Atoh 1诱导哺乳动物耳蜗非感觉细胞转化为HC的能力的转录因子。此外，将研究基因沉默机制的修改，以确定非感觉内耳细胞采用HC表型特征的能力的表观遗传限制。 方法学：将使用内耳感觉上皮细胞的体外培养物和耳蜗噪声损伤的体内研究进行研究。为了鉴定HC保护剂和转录因子，已经开发了创新的高通量方法，以允许快速但有针对性地筛选药物并诱导哺乳动物耳蜗上皮细胞中的基因表达。 在过去的供资期间取得的进展：已确定了耳毒素进入HC的机制;已确定了活性氧积累进入HC的细胞模式，并评价了抗氧化剂治疗;已确定了HC保护的两种新的细胞内途径;已确定了导致耳聋的三种基因突变;已确定了HC发展的关键时期，在此期间可以进行移植;已经鉴定了两种新的转录因子，其增强非感觉耳蜗细胞向HC的转化，并且已经进行了耳蜗感觉上皮的表观遗传操作以增强由病毒载体诱导的基因表达。 临床关系：SNHL的预防和治疗对退伍军人和VA非常重要。SNHL对退伍军人生活质量的影响是巨大的。SNHL和耳鸣也占更多的残疾补偿在VA比任何其他疾病，康复费用很高。拟议的研究旨在开发新的和改进的疗法，以预防和治疗这一重要的健康问题。

DESCRIPTION (provided by applicant): Objectives: Sensorineural hearing loss (SNHL) is strongly associated with many aspects of military service including blast injury. The objectives of this proposal are to improve the prevention and treatment of SNHL in veterans. Research Design: To improve our understanding of cellular processes underlying hair cell (HC) damage and loss, the contributions of molecular isoforms within known HC damage and survival pathways will be evaluated by determining their expression, and by evaluating HC loss in gene knockout mice. To improve SNHL prevention, pharmaceutical agents that can protect cochlear HCs from damage will also be identified. To improve treatment for SNHL, transcription factors that enhance the ability of Atoh1 to induce the conversion of mammalian cochlear non-sensory cells into HCs will be identified. In addition, modifications to mechanisms of gene silencing will be studied to identify epigenetic limitations on the ability of nonsensory inner ear cells to adopt features of the HC phenotype. Methodology: Studies will be performed using in vitro cultures of inner ear sensory epithelia, and in vivo studies of noise damage to the cochlea. For identification of HC protectants and transcription factors, innovative high-throughput methods have been developed to permit rapid, but targeted, screening of pharmaceuticals and induced gene expression in mammalian cochlear epithelia. Progress over the past period of funding: Mechanisms of ototoxin entry into HCs have been identified; cellular patterns of reactive oxygen species accumulation into HCs have been determined and antioxidant treatments evaluated; two novel intracellular pathways of HC protection have been defined; three gene mutations that lead to deafness have been identified; a critical period of HC development in which transplantation is possible has been determined; two novel transcription factors that enhance the conversion of nonsensory cochlear cells into HCs have been identified, and epigenetic manipulation of the cochlear sensory epithelium to enhance gene expression induced by a viral vector has been performed. Clinical Relationship: The prevention and treatment of SNHL is of great importance to veterans and to the VA. The effects of SNHL on veterans' quality of life are substantial. SNHL and tinnitus also account for more disability compensation in the VA than any other disorder, and rehabilitation costs are high. The proposed research is targeted at developing new and improved therapies for prevention and treatment of this important health problem.