Investigations into the mouse olivocochlear system

小鼠橄榄耳蜗系统的研究

基本信息

批准号：
7185813
负责人：
DOUGLAS E VETTER
金额：
$ 37.57万
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 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7185813
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）：最近发现促肾上腺皮质激素释放激素（CRH）受体和尿皮质素（CRH肽家族的成员）分别在外毛细胞和橄榄耳蜗末端表达。虽然已经使用尿皮质素缺陷小鼠对 urocorUn（内耳中表达的唯一已知配体能够激活 CRH 受体）所发挥的作用进行了分析，但对于内耳中 CRH 受体的发育表达模式或作用尚不清楚。耳朵。 CRH 受体是 G 蛋白偶联受体，可刺激 cAMP 第二信使信号级联反应。我们假设 CRH 受体的激活可能代表了一种防止噪音引起的听力损失的现象。作用机制可能包括 sK2 钙激活 apamin 敏感钾通道的磷酸化和失活。为了进一步分析耳蜗中 CRH 系统的形态、其在听力中的功能作用以及防止噪声引起的听力损失，最后评估与 CRH 受体激活相关的细胞作用机制，三个具体目标被提议。首先，我们将建立内耳中 CRH 受体的发育和成人表达模式。成功完成这一特定目标的实验将确定内耳内表达 CRH 受体的细胞的精确身份，并在超结构水平上识别尿皮质素免疫阳性纤维的突触后元件。其次，我们将确定 CRH 在听力中发挥的功能作用，以及它们是否参与保护内耳免受噪声引起的听力损失。这一目标将通过使用缺乏 1 型或 2 型 CRH 受体基因或两者都缺乏的小鼠来实现。最后，我们将使用这些小鼠来确定 CRH 受体基因消融后，cAMP 诱导的外毛细胞靶点磷酸化是否发生变化。这一目标的成功将使我们能够识别由于 CRH 受体激活而磷酸化的各个蛋白质，以及它们在调节正常橄榄耳蜗突触活性中的作用。这将在功能上将尿皮质素激素/CRH 受体和经典的乙酰胆碱神经递质系统连接在一起，形成一个统一的模型，解释基于内耳的噪音引起的听力损失的保护。