CREB-Mediated Survival of Deafferented Auditory Neurons

CREB ​​介导的失传听觉神经元的存活

• 批准号: 6359897
• 负责人: Lance Zirpel
• 金额: $ 29.75万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6359897
• 关键词: acoustic nerve; auditory nuclei; biological signal transduction; cAMP response element binding protein; calcium; calmodulin dependent protein kinase; chick embryo; electroporation; immunocytochemistry; laboratory mouse; neural degeneration; phosphorylation; protein kinase A; sensorineural hearing loss; transfection; western blottings

The proposed experiments are directed at elucidating the mechanism of survival in activity-deprived auditory neurons. As with central neurons in all other sensory systems, brainstem auditory neurons require afferent input for maintenance and survival. Elimination of this input results in the death of 30- 60 percent of cochlear nucleus neurons in neonatal chicks and mice. Thus, the proposed studies concern the role of phosphorylation and activation of the transcription factor calcium/cAMP response element binding protein (CREB) in the subpopulation of cochlear nucleus neurons that survive activity deprivation. The experiments will address two groups of questions about the interactions among activity deprivation, intracellular calcium changes, CREB phosphorylation and activation, and neuronal survival. The hypothesis driving these experiments posits that following activity deprivation cochlear nucleus neurons show increased phophorylation/activation of CREB in the response to increased intracellular calcium. This phosphorylation is mediated by calcium-dependent activation of calcium/calmodulin dependent kinases and protein kinase A. Once phosphorylated, CREB results in the transcription of genes containing the calcium/cAMP response element within their promoter region, and the protein products of some of these genes allow the neurons to survive activity deprivation. The proposed experiments, grouped into two specific aims, will characterize the mechanisms of CREB phosphorylation and the role of this phosphorylation in neuronal survival. Neuronal survival is a critical issue in patients with sensory deficits. A significant fraction of the U.S. population suffers from profound hearing loss of early onset. There is agreement that early intervention is the most effective strategy for successful treatment. Understanding the mechanisms of neuronal survival following early sensorineural hearing loss may influence the success of restorative therapies for the congenitally hearing-impaired. During neural development, critical periods occur in which central structures are more sensitive or receptive to changes in afferent input. One potential benefit to understanding how central neurons survive activity deprivation will be to prolong these critical periods, thus improving success rates of early intervention therapy on patients with congenital hearing deficits. The proposed experiments would contribute information about how central auditory neurons survive in the absence of afferent input.

提出的实验旨在阐明活性剥夺的听觉神经元中生存的机理。 与所有其他感觉系统中的中央神经元一样，脑干听觉神经元需要传入的输入来维持和生存。 消除这种输入导致新生儿雏鸡和小鼠中的30％至60％的耳蜗神经元死亡。 因此，拟议的研究涉及转录因子钙/cAMP反应元件结合蛋白（CREB）的磷酸化和激活在生存活性剥夺的人群中的亚群中的作用。 这些实验将解决有关活性剥夺，细胞内钙变化，CREB磷酸化和激活以及神经元存活之间相互作用的两组问题。 驱动这些实验的假设认为，以下活性剥夺耳蜗神经元表明，在对细胞内钙增加的响应中，CREB的噬蛋白化/激活增加。 这种磷酸化是由钙/钙调蛋白依赖性激酶和蛋白激酶A的钙依赖性激活和蛋白激酶A的介导的。一旦磷酸化，CREB会导致含有启动子区域内包含钙/cAMP反应元件的基因的转录，这些基因的蛋白质产物可以使神经元的蛋白质产物生存活性活性。 所提出的实验分为两个特定目标，将表征CREB磷酸化的机制以及该磷酸化在神经元存活中的作用。神经元存活是感官缺陷患者的关键问题。 美国人群中很大一部分遭受了早期发作的严重听力丧失。 达成共识，早期干预是成功治疗的最有效策略。 了解早期感官听力损失后神经元生存的机制可能会影响先天听力受损的恢复性疗法的成功。 在神经发育过程中，发生关键时期，其中中央结构对传入输入的变化更敏感或接受。 了解中枢神经元如何在活动剥夺中生存的一个潜在好处是延长这些关键时期，从而提高了先天性听力缺陷患者的早期干预疗法的成功率。 提出的实验将贡献有关中央听觉神经元如何在没有传入输入的情况下生存的信息。