Protection from Noise Induced Hearing Loss - Genetic and Drug Induction of HSPs

防止噪音引起的听力损失 - HSP 的遗传和药物诱导

• 批准号: 8789356
• 负责人: David C Kohrman
• 金额: $ 19.24万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-06 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789356
• 关键词: Acoustic Nerve; Acquired Deafness; Address; Affect; Aminoglycosides; Animal Model; Animals; Antioxidants; Auditory; Auditory Brainstem Responses; Cisplatin; Clinical Trials; Cochlea; Collaborations; Cultured Cells; Disease; Drosophila genus; Ear; Gene Targeting; Generations; Genes; Genetic; Genetically Engineered Mouse; HSF1; Hair Cells; Health; Hearing; Heat shock proteins; Heat-Shock Response; Heating; Human; Huntington Disease; Hyperthermia; Incentives; Incidence; Labyrinth; Mammals; Methods; Military Personnel; Modeling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Noise; Noise-Induced Hearing Loss; Pathway interactions; Pharmaceutical Preparations; Protein Isoforms; Proteins; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Route; SF1; Services; Stress; System; Testing; Therapeutic; Time; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Trauma; Ulcer; Universities; Up-Regulation; Workplace; antioxidant therapy; biological adaptation to stress; cell type; cellular pathology; clinical application; cytotoxicity; efficacy evaluation; efficacy testing; fly; geranylgeranylacetone; hearing impairment; immunocytochemistry; in vivo; mouse model; mutant; novel strategies; ototoxicity; ototoxin; polyglutamine; pre-clinical; research clinical testing; response; small molecule; transcription factor

DESCRIPTION (provided by applicant): The proposed studies address a significant health issue, the high incidence of acquired deafness from noise overstimulation that can result from recreational and workplace-related activities and from service in the military. Activation of the classic stress response by up-regulation of heat shock proteins (Hsps) has been very effective in protecting the inner ear from noise induced hearing loss in animal models. However, a major roadblock to clinical applicability is the lack of an appropriate method to induce the heat shock response in the inner ear in humans. We propose two parallel approaches to further evaluate the heat shock response as a protective strategy against noise trauma in the cochlea and move closer to an efficient therapeutic method. In one approach, we will exploit the findings of a recent screen for molecules that activate HSF1, the transcription factor that is the master regulator of the heat shock response. This screen identified a compound (HSF1A) that efficiently activates the pre-existing pool of HSF1 and results in up-regulation of target Hsp genes. This HSF1 activation reduces the levels of protein damage and cytotoxicity in cultured cell and fly models of neurodegenerative disease. Our preliminary studies were the first evaluation of the efficacy of HSF1A in vivo in the mammal and showed that application of HSF1A induces up-regulation of Hsps in the cochlea. In a second approach, we will investigate an alternative mode of heat shock activation through generation of transgenic mice that conditionally express an activated form of HSF1 (HsfTgAct) in the cochlea and thereby permit a temporary increase in the overall pool of HsfTgAct and promote a more robust heat shock response. We propose to compare the efficiencies of the small molecule and transgenic methods to activate HSP target genes in the ear and to evaluate their relative abilities to protect auditory function from noise trauma. These studies will take a critical step in moving a stalled therapeutic approach towards clinical application. Evidence of significant protection would provide justification for additional pre-clinical animal trials, a strong incentive for additional SF1 activator screens, and a route to testing efficacy in humans. An efficient method to activate the heat shock response in the inner ear could not only provide protection from noise-induced hearing loss for millions of people but would also have application to protection from ototoxins, affecting millions more.

描述（由申请方提供）：拟定研究解决了一个重要的健康问题，即娱乐和工作场所相关活动以及军队服役导致的噪声过度刺激导致的获得性耳聋的高发病率。在动物模型中，通过上调热休克蛋白（Hsps）激活经典的应激反应在保护内耳免受噪声诱导的听力损失方面非常有效。然而，临床应用的一个主要障碍是缺乏适当的方法来诱导人类内耳中的热休克反应。我们提出了两种平行的方法，以进一步评估热休克反应作为耳蜗噪声创伤的保护策略，并更接近一种有效的治疗方法。在一种方法中，我们将利用最近筛选激活HSF 1的分子的结果，HSF 1是热休克反应的主要调节因子。该筛选鉴定了一种化合物（HSF1A），其有效激活预先存在的HSF1库并导致靶Hsp基因的上调。这种HSF1激活降低了神经退行性疾病的培养细胞和苍蝇模型中的蛋白质损伤和细胞毒性水平。我们的初步研究是第一次评估HSF1A在哺乳动物体内的功效，并表明HSF1A的应用诱导耳蜗中Hsps的上调。在第二种方法中，我们将通过产生转基因小鼠来研究热休克激活的替代模式，所述转基因小鼠在耳蜗中有条件地表达激活形式的HSF1（HsfTgAct），从而允许HsfTgAct的总体库暂时增加，并促进更稳健的热休克反应。我们建议比较小分子和转基因方法激活耳部HSP靶基因的效率，并评估它们的相对保护能力。 听觉功能受损这些研究将迈出关键的一步，将停滞不前的治疗方法推向临床应用。显著保护的证据将为额外的临床前动物试验提供理由，为额外的SF1激活剂筛选提供强有力的激励，并为在人体中测试疗效提供途径。一种激活内耳热休克反应的有效方法不仅可以为数百万人提供保护，使其免受噪音引起的听力损失，而且还可以应用于保护耳毒素，影响数百万人。