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

基本信息

批准号：
8636712
负责人：
David C Kohrman
金额：
$ 23.33万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-06 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8636712
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 public health relevance research clinical testing response small molecule transcription factor

项目摘要

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（由申请人提供）：拟议的研究解决了一个重大的健康问题，这是由于噪音过度刺激而获得的耳聋发病率可能是由娱乐和工作场所相关的活动以及军事服务的。通过上调热休克蛋白（HSP）激活经典应力反应，在保护内耳免受动物模型中噪声诱导的听力损失方面非常有效。但是，临床适用性的主要障碍是缺乏适当的方法来诱导人类内耳的热冲击反应。我们提出了两种平行的方法，以进一步评估热冲击响应，作为针对耳蜗中噪声创伤的保护策略，并更接近有效的治疗方法。在一种方法中，我们将利用激活HSF1的分子的最新筛选结果，该分子是热休克响应的主要调节剂的转录因子。该屏幕确定了一个有效激活HSF1库的化合物（HSF1A），并导致靶HSP基因的上调。该HSF1激活降低了培养细胞和神经退行性疾病的蝇fly模型中蛋白质损伤和细胞毒性的水平。我们的初步研究是对HSF1A体内疗效的首次评估，并表明HSF1A的应用诱导了HSP在耳蜗中的上调。在第二种方法中，我们将通过产生的转基因小鼠来研究一种替代热冲击激活的模式，该小鼠在耳蜗中有条件地表达激活形式的HSF1（HSFTGACT），从而允许HSFTGACT的总体池暂时增加并促进更强大的热冲击响应。我们建议比较小分子和转基因方法的效率，以激活耳朵中的HSP靶基因并评估其保护其相对能力噪声创伤的听觉功能。这些研究将在将停滞的治疗方法转向临床应用方面迈出关键的一步。具有重大保护的证据将为其他临床前动物试验，对其他SF1激活筛网的强烈动力以及测试人类测试疗效的途径提供理由。一种有效的方法来激活内耳中的热冲击反应不仅可以为数百万人提供噪音引起的听力损失的保护，而且还可以保护远离耳毒素，从而影响数百万。