Cochlear Homeostasis

耳蜗稳态

• 批准号: 7380021
• 负责人: JOE C ADAMS
• 金额: $ 31.09万
• 依托单位: MASSACHUSETTS EYE AND EAR INFIRMARY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380021
• 关键词: Acoustic Trauma; Acoustics; Adult; Age; Apoptotic; Bacterial Toxins; CBA/CaJ Mouse; Cells; Cellular Stress Response; Class; Cochlea; Cochlear duct; Complex; Ear; Elements; Exposure to; Family; Funding; Gene Expression; Genes; Glial Growth Factor; Hair Cells; Hearing; Histopathology; Homeostasis; Immunohistochemistry; Inherited; Injury; Knockout Mice; Labyrinth; Ligaments; Maintenance; Mitotic; Modeling; Molecular; Mus; NF-kappa B; Nature; Nerve Growth Factor Receptors; Noise; Organ; Organ of Corti; Outer Hair Cells; Pathway interactions; Pattern; Pharmaceutical Preparations; Play; Process; Production; Proteins; Receptor Up-Regulation; Reporter; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Sensory; Signal Transduction; Stress; Testing; Time; Tissues; Transcriptional Activation; Transgenic Mice; Transgenic Organisms; Translations; Trauma; Up-Regulation; Upper arm; Week; age related; attenuation; conditioning; deafness; middle age; mouse model; neglect; neurotrophic factor; receptor; response; sound; stressor; transcription factor

The post mitotic nature of cochlear sensory and non-sensory cells requires protection against apoptotic processes for lifetime maintenance of normal cochlear function. The diverse specializations of cochlear cells dictates that their anti-apoptotic pathways, which respond to cell specific stresses are correspondingly diverse. In the past funding period, we accumulated evidence that spiral ligament cells' responses to cochlear stresses play a key role in protection of the entire organ. A major player in anti-apoptotic pathways is a family of transcription factors known as NFkappaB (NFkappaB). We used a transgenic reporter mouse to show that it is spiral ligament fibrocytes, not cells within the organ of Corti, that show robust NFkappaB activation in response to noise exposure. Similarly, we showed that the receptor for a growth factor (GDNF), known to protect sensory cells from noise and ototoxic drugs, is not present on hair cells, but in spiral ligament fibrocytes, where it's expression is robustly up-regulated following a non-traumatic noise exposure known to protect the ear from subsequent acoustic injury. We hypothesize that noise-induced up-regulation of this receptor is downstream of NFkappaB activation, and that this up-regulation in the spiral ligament is key to the induction of cochlear protection via pre-exposure to noise stressors, and to the age-related difference in vulnerability to noise seen in normal-hearing CBA/CalphaJ mice. In this proposal, we test these hypotheses (1) by using a well-established mouse model of noise-induced protection from noise trauma to compare the time course of induction and reduction of protection with the time course of noise-induced changes in cochlear expression and translation of NFkappaB, the GDNF receptor, and other related stress genes, (2) by testing the effects of selectively blocking noise-induced NFkappaB activation in spiral ligament fibrocytes using a transgenic mouse in which a key upstream activator of NFkappaB has been eliminated and (3) by comparing noise-induced changes in cochlear expression and translation of NFkappaB, the GDNF receptor, and other related stress genes in vulnerable young mice vs. resistant middle-aged mice. The results of these studies will clarify the role of NFkappaB, an important arm of the complex cascade of anti-apoptotic stress-induced gene expression pathways, in the induction of cochlear protected states and will also add to our understanding of the functional role(s) of the spiral ligament fibrocytes, which are now known to be a major locus of cochlear histopathology in a variety of inherited and acquired types of deafness.

耳蜗感觉细胞和非感觉细胞的有丝分裂后性质需要保护免于凋亡过程以终身维持正常耳蜗功能。耳蜗细胞的多样性特化决定了它们对细胞特异性应激作出响应的抗凋亡途径相应地是多样的。在过去的资助期间，我们积累了证据，证明螺旋韧带细胞对耳蜗应力的反应在保护整个器官方面发挥着关键作用。抗凋亡途径中的主要参与者是称为NF κ B（NF κ B）的转录因子家族。我们使用转基因报告小鼠来表明，是螺旋韧带纤维细胞，而不是Corti器官内的细胞，在噪声暴露时显示出强大的NF κ B激活。同样，我们发现，已知保护感觉细胞免受噪音和耳毒性药物影响的生长因子（GDNF）受体不存在于毛细胞上，而是存在于螺旋韧带纤维细胞中，在非创伤性噪音暴露后，其表达强烈上调已知保护耳朵免受随后的声损伤。我们假设噪声诱导的这种受体的上调是NF κ B激活的下游，并且螺旋韧带中的这种上调是通过预暴露于噪声应激源诱导耳蜗保护的关键，并且是听力正常的CBA/CalphaJ小鼠中所见的噪声易感性的年龄相关差异的关键。在本提案中，我们测试了这些假设（1）通过使用成熟的噪音诱导的噪音创伤保护小鼠模型来比较诱导和减少保护的时间过程与噪音诱导的耳蜗表达变化的时间过程和翻译NFkappaB、GDNF受体和其他相关应激基因，（2）通过使用其中NF κ B的关键上游激活物已被消除的转基因小鼠测试选择性阻断螺旋韧带纤维细胞中噪声诱导的NF κ B激活的作用，和（3）通过比较噪声-NF κ B的激活，在脆弱的年轻小鼠和抵抗的中年小鼠中，诱导耳蜗表达和NF κ B、GDNF受体和其他相关应激基因翻译的变化。这些研究的结果将阐明NF κ B在诱导耳蜗保护状态中的作用，NF κ B是抗凋亡应激诱导的基因表达途径的复杂级联的重要分支，并且还将增加我们对螺旋韧带纤维细胞的功能作用的理解，现在已知螺旋韧带纤维细胞是各种遗传性和获得性耳聋中耳蜗组织病理学的主要位点。