Endogenous Modulation of Cochlear Injury

耳蜗损伤的内源性调节

基本信息

批准号：
9231405
负责人：
LEONARD P RYBAK
金额：
$ 30.98万
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 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9231405
关键词：
Affect Afferent Neurons Agonist Animal Experiments Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Bilateral Biological Assay Breast CNR1 gene CNR2 gene Cancer Patient Cannabinoids Capsaicin Capsicum Cells Chemotherapy-Oncologic Procedure Child Cisplatin Clinical Cochlea Data Dose Ear Evoked Potentials, Auditory, Brain Stem Future Gene Expression Profiling Genes Head and Neck Cancer Human In Vitro Inflammatory Inflammatory Response Injectable Injection of therapeutic agent Injury Interleukin-1 beta Laboratories Labyrinth Link Malignant Neoplasms Mediating Molecular Oral Oral Administration Ovarian Oxidative Stress Pathway interactions Pharmacotherapy Phosphorylation Preparation Protein p53 Proteins RNA Rattus Reporting Research Research Proposals Resistance Role SCID Mice STAT protein STAT1 gene STAT3 gene Scanning Electron Microscopy Social Development Speech Development TNF gene TP53 gene TRPV1 gene TdT-Mediated dUTP Nick End Labeling Assay Testing Time Tissues Transcript Tumor Cell Line Tumor Suppressor Proteins Universities Up-Regulation Western Blotting analog cancer cell cancer therapy cannabinoid receptor cognitive development cytokine differential expression experimental study functional genomics hearing impairment immunocytochemistry in vivo interest novel novel therapeutics ototoxicity preconditioning prevent public health relevance receptor receptor expression relating to nervous system tumor

项目摘要

DESCRIPTION (provided by applicant): Cisplatin is a critical component of current chemotherapy regimens. Unfortunately, cisplatin frequently causes ototoxicity that is bilateral and irreversible. This is particularly challenging in young children in whom hearing loss severely hampers speech, cognitive and social development. Thus, there is an urgent need for new drugs to reduce cisplatin ototoxicity. Recent studies from our laboratory have shown that a single transtympanic injection of capsaicin (TRPV1 agonist) produced transient hearing loss and temporary increases in inflammatory cytokines. Surprisingly, pretreatment with transtympanic capsaicin alleviated cisplatin ototoxicity. Preliminary data show that oral capsaicin also reduces cisplatin-induced auditory brain stem response (ABER) threshold shifts. Our in vitro studies suggest that capsaicin's "preconditioning" effect results from transient STAT1 up-regulation. Activation of STAT1 by capsaicin may modify or sequester STAT1, preventing its interaction with p53 when cochlear cells are subsequently challenged by cisplatin. Alternatively, capsaicin could activate STAT1 (i.e. increase its phosphorylation) differently from cisplatin. Capsaicin could also activate cytoprotective STAT proteins (such as STAT3). Capsaicin can also increase cannabinoid (CB) expression in the cochlea, which can be cytoprotective. Preliminary experiments in UB/OC1 cells show that capsaicin up-regulates CB receptors in these cells. Experiments in aim1 should confirm the efficacy of oral capsaicin against cisplatin ototoxicity and the subsequent 3 aims will elucidate mechanisms of protection. Aim 2 will determine the molecular basis of capsaicin-mediated protection against cisplatin ototoxicity. The hypothesis is that capsaicin activates STAT1 (by mediating Ser727 and Tyr701 phosphorylation) which sequesters (or down-regulates) it, thereby decreasing the availability of STAT1 accessible for activation by cisplatin. Aim 3 will test the hypothesis that capsaicin-mediated protection against cisplatin ototoxicity by activation, or increasing the expression, of CB receptors in the cochlea. CB activation reduces cisplatin ototoxicity in vitro and has demonstrated anti-inflammatory and neuroprotective effects in numerous reports. Aim 4 will test the hypothesis that Gene Array will demonstrate changes in genes of interest in the cochlea of rats treated with capsaicin, cisplatin and cisplatin plus capsaicin. Aim 5 will determine whether capsaicin interferes with or actually enhances the antitumor efficacy of cisplatin. This research will offer great promise to provide novel protective oral treatments to ameliorate cisplatin ototoxicity.

描述（由申请人提供）：顺铂是当前化学疗法方案的关键组成部分。不幸的是，顺铂经常引起双侧和不可逆的耳毒性。对于幼儿，听力损失严重阻碍了言论，认知和社会发展，这尤其具有挑战性。因此，迫切需要新药降低顺铂耳毒性。我们实验室的最新研究表明，辣椒素（TRPV1激动剂）单次跨抑制注射会导致炎症细胞因子的短暂性听力损失和暂时增加。出乎意料的是，用跨抑制辣椒素预处理可缓解顺铂耳毒性。初步数据表明，口服辣椒素还减少了顺铂诱导的听觉脑干反应（ABER）阈值偏移。我们的体外研究表明辣椒素的“预处理”效应是瞬时STAT1上调引起的。辣椒素对STAT1的激活可能会修饰或隔离STAT1，从而阻止其与p53的相互作用，当时是通过顺铂挑战耳蜗。另外，辣椒素可以与顺铂不同地激活STAT1（即增加其磷酸化）。辣椒素还可以激活细胞保护统计蛋白（例如STAT3）。辣椒素还可以增加耳蜗中的大麻素（CB）表达，这可能是细胞保护的。 UB/OC1细胞中的初步实验表明，辣椒素会上调这些细胞中的CB受体。 AIM1中的实验应确认口服辣椒素针对顺铂耳毒性的功效，随后的3个目标将阐明保护机制。 AIM 2将确定辣椒素介导的针对顺铂耳毒性的保护的分子基础。假设是辣椒素激活STAT1（通过介导Ser727和Tyr701磷酸化），从而隔离（或下调），从而降低了STAT1的可用性，可通过顺铂访问以激活。 AIM 3将检验以下假设：辣椒素介导的保护通过激活或增加耳蜗中CB受体的表达来抗异铂耳毒性。 CB激活在体外降低了顺铂耳毒性，并在许多报告中表现出抗炎和神经保护作用。 AIM 4将检验以下假设：基因阵列将证明用辣椒素，顺铂和顺铂加辣椒素治疗的大鼠的耳蜗中感兴趣的基因变化。 AIM 5将确定辣椒素是否会干扰或实际上增强顺铂的抗肿瘤功效。这项研究将提供巨大的希望，提供新型的保护性口服治疗，以改善顺铂耳毒性。