Investigations into the mouse olivocochlear system

小鼠橄榄耳蜗系统的研究

基本信息

批准号：
7365153
负责人：
DOUGLAS E VETTER
金额：
$ 37.08万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7365153
关键词：
Ablation Acetylcholine Acoustic Trauma Address Adult Apamin Binding Calcium Cells Cochlea Complement Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Cyclic AMP Data Defect Development Elements Event Family Fiber G-Protein-Coupled Receptors Gene Expression Genes Hearing Hormone Receptor Hormones Individual Investigation Ion Channel Knockout Mice Labyrinth Lateral Ligands Link Modeling Mus Nature Nerve Neurotransmitter Receptor Neurotransmitters Noise-Induced Hearing Loss Organ of Corti Organogenesis Outer Hair Cells Pattern Peptides Phosphorylation Play Potassium Channel Predisposition Proteins Publishing Purpose RNA Splicing RRM2 gene Receptor Activation Receptor Gene Role Role playing therapy Second Messenger Systems Series Signal Transduction Synapses System Time Variant base corticotropin releasing factor-binding protein desensitization design ganglion cell member novel postsynaptic receptor research study second messenger spiral ganglion success urocortin

项目摘要

DESCRIPTION (provided by applicant): Corticotropin releasing hormone (CRH) receptors, and urocortin, a member of the CRH family of peptides, has recently been discovered expressed in outer hair cells and olivocochlear terminals, respectively. While analysis of the role played by urocorUn, the only known ligand expressed in the inner ear capable of activating the CRH receptors, has been analyzed using urocortin deficient mice, nothing is known of the developmental expression pattern or role of the CRH receptors in the inner ear. The CRH receptors are G protein coupled receptors, and stimulate the cAMP second messenger-signaling cascade. We hypothesize that activation of the CRH receptors may represent one phenomenon underlying protection from noise induced hearing loss. The mechanisms of action may include phosphorylation and inactivation of the sK2 calcium-activated apamin-sensitive potassium channel. In order to further analyze the morphological aspects of the CRH system in the cochlea, its functional role in hearing and protection from noise induced hearing loss, and finally, to assess the cellular mechanisms of action associated with activation of the CRH receptors, three specific aims are proposed. First, we will establish the developmental and adult expression pattern of the CRH receptors in the inner ear. Successful completion of the experiments of this specific aim will establish the precise identity of the cells within the inner ear that express the CRH receptors, and identify the postsynaptic elements of the urocortin immunopositive fibers at the ultra structural level. Second, we will establish the functional roles CRH plays in hearing, and whether they participate in protection of the inner ear from noise induced hearing loss. This aim will be accomplished using mice that lack the gene for either the type 1 or the type 2 CRH receptor, or that lack both. Finally, we will use these mice to establish whether there are alterations in cAMP induced phosphorylation of targets in the outer hair cells following CRH receptors gene ablation. Success in this aim will allow us to identify individual proteins phosphorylated due to activation of the CRH receptors, as well as their role in modulating normal olivocochlear synaptic activity. This will functionally link the urocortin hormone/CRH receptor and classical ACh neurotransmitter systems together in a unified model explaining inner ear based protection from noise induced hearing loss.

描述（由申请人提供）：最近在外毛细胞和橄榄石末端表达的CRH家族的尿素蛋白释放激素（CRH）受体和尿道素蛋白分别被发现。虽然对Urocorun扮演的作用的分析，但已经使用尿皮质素缺乏小鼠分析了能够激活CRH受体的内耳中唯一已知的配体，但对CRH受体在内耳中的发育表达模式或作用一无所知。 CRH受体是G蛋白偶联受体，并刺激营地第二信号级联。我们假设CRH受体的激活可能代表了噪声引起的听力损失的一种潜在保护的现象。作用机制可能包括SK2钙激活的阿昔蛋白敏感钾通道的磷酸化和灭活。为了进一步分析耳蜗中CRH系统的形态学方面，其在听力和保护噪声引起的听力损失中的功能作用，最后评估与CRH受体激活相关的细胞作用机制，提出了三个具体目标。首先，我们将建立内耳中CRH受体的发育和成人表达模式。成功完成该特定目标的实验将建立表达CRH受体的内耳中细胞的精确身份，并确定在超结构水平上泌尿诺素免疫阳性纤维的突触后元素。其次，我们将确定CRH在听力中的功能作用，以及它们是否参与内耳的保护免受噪声引起的听力损失。使用缺少1型或2型CRH受体的基因的小鼠或两者都缺乏基因的小鼠来实现此目标。最后，我们将使用这些小鼠来确定CRH受体基因消融后，cAMP诱导的外毛细胞中靶标的磷酸化是否发生了变化。在此目标中的成功将使我们能够鉴定由于CRH受体的激活而磷酸化的单个蛋白质，以及它们在调节正常橄榄石突触活性中的作用。这将在统一的模型中将泌尿肌素激素/CRH受体和经典ACH神经递质系统连接起来，以解释基于内耳的保护，从而解释了基于内耳的保护，以免噪声诱导的听力损失。