Function and regulation of acid-sensing ion channels in corneal neurons

角膜神经元酸敏离子通道的功能和调节

• 批准号: 8676511
• 负责人: John Bankston
• 金额: $ 9.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676511
• 关键词: ASIC channel; Acidosis; Acids; Adult; Affect; Afferent Neurons; Age; Biological Models; Bradykinin; Calcium; Cell Surface Receptors; Cell surface; Chemicals; Cornea; Cutaneous; Detection; Development; Dinoprostone; Electrophysiology (science); Esthesia; Eye; Eye diseases; Family; Frequencies; G-Protein-Coupled Receptors; Genes; Goals; Heating; Homo; Immunohistochemistry; Infection; Inflammation; Inflammatory; Injury; Ion Channel; Ions; Irritants; Ischemia; Kinins; Learning; Lipids; Measurement; Mechanics; Mediating; Membrane; Metals; Molecular; Mus; Nerve; Neurons; Nociception; Nociceptors; Pain; Pain management; Pathway interactions; Patients; Peripheral Nervous System; Pharmacology; Phosphatidylinositols; Phospholipase; Phosphoric Monoester Hydrolases; Play; Polyamines; Preparation; Process; Property; Prostaglandins; Protein Isoforms; Proteins; Protons; RNA Splicing; Receptor Protein-Tyrosine Kinases; Regulation; Relative (related person); Reporting; Role; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Sodium; Stimulus; Structure of trigeminal ganglion; Symptoms; Syndrome; Temperature; Testing; Tissues; Toxin; Work; aqueous; base; blink reflexes; desensitization; epithelial Na+ channel; eye dryness; injured; lacrimal; ocular pain; ocular surface; public health relevance; receptor coupling; response; sensor; tool; trafficking; tumor growth; voltage

DESCRIPTION (provided by applicant): Nociception, the process through which a subset of sensory neurons detects noxious (painful) stimuli, is an important but poorly understood process in the trigeminal ganglion neurons that innervate the cornea. These neurons respond to a wide array of irritating stimuli including heat, cooling, mechanical force, and chemicals including protons and inflammatory molecules. Inflammation in the cornea, a result of damage to the neurons that innervate it, often leads to sensitization of those neurons. The response to noxious stimuli and to inflammatory molecules is mediated in large part by ion channels, G-protein coupled receptors (GPCRs), and receptor tyrosine kinases (RTKs). A better understanding of the ion channels involved in ocular pain and the hyperalgesic sensory pathway would be important for development of more targeted pain management tools. The goal of this work is to understand the cellular and molecular mechanisms by which GPCRs and RTKs regulate the function, trafficking, and expression of ion channels during pain transduction. To do this, I will use acid-sensing ion channels (ASICs) as a model system because they have been shown to mediate pain in response to tissue acidification and they are regulated during inflammation in cutaneous sensory neurons. These important channels for pain sensation are poorly studied in the cornea despite the fact that corneal neurons display a strong response to changes in pH. In this proposal, I plan to identify the proteins responsible for detection of acidic pH in corneal neurons. To do this I will learn to record directly from corneal nerve terminals. In addition, I wil examine the effects of pro-inflammatory molecules like kinins and prostaglandins of the acid-sensitive currents. Many of these inflammatory molecules trigger the activation of the phospholipase c signaling pathway, which reduces the amount of the phosphoinositide, PI(4,5)P2, in the membrane. Thus, I will examine the role phosphoinositides play in corneal neurons and in the regulation of ASICs.

描述（由申请人提供）：痛觉是一种感觉神经元子集检测有害（疼痛）刺激的过程，是支配角膜的三叉神经节神经元中一个重要但鲜为人知的过程。这些神经元对各种刺激性刺激作出反应，包括热、冷、机械力和化学物质，包括质子和炎症分子。角膜的炎症是支配它的神经元受损的结果，通常会导致这些神经元的敏感化。对有害刺激和炎症分子的反应在很大程度上是由离子通道、g蛋白偶联受体（gpcr）和受体酪氨酸激酶（rtk）介导的。更好地了解参与眼痛和痛觉感觉通路的离子通道对于开发更有针对性的疼痛管理工具非常重要。这项工作的目的是了解GPCRs和RTKs在疼痛转导过程中调节离子通道的功能、运输和表达的细胞和分子机制。为此，我将使用酸感应离子通道（asic）作为模型系统，因为它们已被证明在组织酸化反应中介导疼痛，并且在皮肤感觉神经元的炎症过程中受到调节。尽管角膜神经元对pH的变化表现出强烈的反应，但这些重要的痛觉通道在角膜中的研究很少。在本提案中，我计划鉴定角膜神经元中负责检测酸性pH的蛋白质。为此，我将学习直接从角膜神经末梢进行记录。此外，我将研究促炎分子如激肽和前列腺素对酸敏感电流的影响。许多这些炎症分子触发磷脂酶c信号通路的激活，从而减少膜中磷酸肌肽PI(4,5)P2的数量。因此，我将研究磷酸肌苷在角膜神经元和asic调控中的作用。