Endogenous Modulation of Cochlear Injury

耳蜗损伤的内源性调节

基本信息

批准号：
7849529
负责人：
LEONARD P RYBAK
金额：
$ 24.49万
依托单位：
SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7849529
关键词：
Address Adverse effects Antioxidants Attenuated Auditory Brainstem Responses Cancer Patient Cancer Survivor Cell Death Cell Line Cells Cisplatin Clinical Cochlea Dose Drug usage Enzymes Extracellular Signal Regulated Kinases Future Gene Expression Genes In Vitro Injury Investigation JUN gene Kidney Laboratories Lead MAPK14 gene Malignant Neoplasms Mediating Mediator of activation protein Messenger RNA Methods Mitogen-Activated Protein Kinases NADPH Oxidase Natural regeneration Organ of Corti Outer Hair Cells Oxidative Stress Pathway interactions Pharmaceutical Preparations Phosphotransferases Plasmid Cloning Vector Production Protective Agents Protein Isoforms Proteins Quality of life Rattus Reactive Oxygen Species Receptor Activation Research Scanning Electron Microscopy Signal Pathway Signaling Molecule Small Interfering RNA Stress Superoxides Testing Thioctic Acid Toxic effect Up-Regulation Viral Western Blotting cancer therapy capsazepine chemotherapeutic agent functional loss ganglion cell hearing impairment human CYBA protein in vivo indexing inhibitor/antagonist insight killings mRNA Expression novel novel strategies novel therapeutic intervention ototoxicity prevent programs protective effect protein expression rat KIM-1 protein receptor repaired research study response round window spiral ganglion vanilloid receptor subtype 1

项目摘要

DESCRIPTION (provided by applicant): Cisplatin is a potent chemotherapeutic agent widely used to treat malignant neoplasms. Side effects, like ototoxicity compromise the quality of life of cancer survivors. Cisplatin increases formation of reactive oxygen species (ROS) in the cochlea. A unique isoform of NADPH oxidase, NOX-3, is present in rat cochlea. This enzyme generates superoxide radicals that can damage outer hair cells (OHCs), leading to hearing loss. ROS can activate cochlear genes that may be protective or harmful. Protective molecules may include a novel protein, kidney injury molecule (KIM)-1. It is induced in kidney by cisplatin. This molecule may enhance repair and regeneration of proximal tubule cells. Our laboratory was the first to show KIM-1 in the cochlea and its induction by cisplatin. ROS may up-regulate KIM-1. It is unknown whether this protein protects the cochlea from cisplatin. ROS resulting from cisplatin may also increase expression of potentially harmful transient receptor potential vanilloid 1 receptors (TRPV1). Activation of NOX-3 and TRPV1 may overwhelm cochlear antioxidant defenses, leading to cell death. Experiments in this application seek to more precisely define mechanisms of cisplatin ototoxicity in order to find ways to minimize toxicity. Studies proposed will utilize a cochlear cell line (UB/OC-1) and parallel studies in rats to address three specific aims to: 1) investigate mechanisms of NOX-3 activation by cisplatin in the cochlea; 2) determine whether expression of KIM-1 confers protection against cisplatin ototoxicity and to determine potential mechanisms of its induction; and 3) study whether TRPV1 contributes to cisplatin ototoxicity and to determine mechanisms of its induction. For aim 1, we will administer systemically the antioxidant lipoic acid or short-interfering RNAs (siRNAs) on the round window (RW) to block activation of NOX-3 by cisplatin. In aim 2, we will use RW application of inhibitors of signaling molecules to see if they are involved in KIM-1 induction; and RW application of siRNA for KIM-1 to see if cisplatin ototoxicity increases. For aim 3, we will investigate whether RW application of the TRPV1 antagonist, capsazepine, protects against cisplatin ototoxicity. We will also examine effects of RW administration of siRNA against TRPV1 to see whether this prevents cisplatin ototoxicity. This research could provide new insights into mechanisms of cisplatin ototoxicity and novel therapeutic approaches to ameliorate cisplatin ototoxicity. Cisplatin causes hearing loss in a large percentage of cancer patients who receive this drug to cure their cancer. It would be of great benefit to cancer survivors if a treatment could be discovered that would prevent hearing loss without interfering with the cancer killing effects of cisplatin. This research seeks to discover new potential treatments to reduce the side effect of hearing loss resulting from the treatment of cancer with the drug cisplatin. Cisplatin causes hearing loss in a large percentage of cancer patients who receive this drug to cure their cancer.

描述（由申请人提供）：顺铂是一种有效的化学治疗剂，广泛用于治疗恶性肿瘤。副作用，例如耳毒性损害了癌症幸存者的生活质量。顺铂增加了耳蜗中活性氧（ROS）的形成。大鼠耳蜗中存在NADPH氧化酶Nox-3的独特同工型。这种酶会产生可能损害外毛细胞（OHC）的超氧化物自由基，从而导致听力损失。 ROS可以激活可能具有保护性或有害的人工耳蜗基因。保护性分子可能包括一种新型蛋白质，肾损伤分子（KIM）-1。它是由顺铂诱导的。该分子可以增强近端小管细胞的修复和再生。我们的实验室是第一个在耳蜗中展示KIM-1的实验室及其诱导的实验室。 ROS可能会上调Kim-1。尚不清楚该蛋白是否保护耳蜗免受顺铂的影响。用顺铂产生的ROS还可能增加潜在有害的瞬态受体电位香草素1受体（TRPV1）的表达。 NOX-3和TRPV1的激活可能会压倒人工耳蜗抗氧化剂防御，导致细胞死亡。该应用中的实验试图更精确地定义顺铂耳毒性的机制，以找到最小化毒性的方法。提出的研究将利用大鼠的耳蜗细胞系（UB/OC-1）和平行研究来解决以下三个特定目的：1）研究Cisplatin在耳蜗中的NOX-3激活机制； 2）确定KIM-1的表达是否赋予了对顺铂耳毒性的保护并确定其诱导的潜在机制； 3）研究TRPV1是否有助于顺铂耳毒性并确定其诱导的机制。对于AIM 1，我们将在圆窗（RW）上系统地管理抗氧化剂lipoic酸或短裂RNA（siRNA），以阻止顺铂的Nox-3激活。在AIM 2中，我们将使用信号分子抑制剂的RW应用来查看它们是否参与KIM-1诱导。 siRNA用于KIM-1的RW应用，以查看顺铂耳毒性是否增加。对于AIM 3，我们将研究RW对TRPV1拮抗剂辣椒素的应用是否可以防止顺铂耳毒性。我们还将检查RW给药siRNA对TRPV1的影响，以查看这是否可以防止顺铂耳毒性。这项研究可以提供有关顺铂耳毒性机制和新型治疗方法的新见解，以改善顺铂耳毒性。顺铂会导致大量接受该药物治愈其癌症的癌症患者的听力损失。如果可以发现可以防止听力损失的治疗而不会干扰顺铂的癌症杀伤作用，那么这将对癌症幸存者有很大的好处。这项研究旨在发现新的潜在治疗方法，以减少因药物顺铂治疗癌症而导致听力损失的副作用。顺铂会导致大量接受该药物治愈其癌症的癌症患者的听力损失。