Characterizing the protective effects of caffeine and other natural products in a

表征咖啡因和其他天然产物的保护作用

基本信息

批准号：
8687540
负责人：
ALLISON B COFFIN
金额：
$ 44.48万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-03 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8687540
关键词：
Acoustic Nerve Adenosine Aging Aminoglycoside Antibiotics Aminoglycosides Antibiotics Attenuated Auditory Biological Factors Biological Models Brain Caffeine Cell Death Cells Cellular biology Cessation of life Chemicals Clinic Clinical Cytoprotection Data Development Dissection Epithelial Cells Exposure to Genetic Gentamicins Goals Hair Cells Hearing Human Image Infection Knowledge Labyrinth Lead Learning Libraries Life Marines Mediating Medicine Modeling Molecular Neomycin Neurons Neuroprotective Agents Noise Parkinson Disease Patients Pharmaceutical Preparations Plant alkaloid Plants Play Prevention Property Purinergic P1 Receptors Research Research Personnel Role Ruthenium Ben Safety Schedule Seizures Sensory Sensory Hair Series Signal Transduction Source Students Study models System Techniques Testing Therapeutic Time Toxin Training Translating Work Zebrafish aminoglycoside-induced ototoxicity auditory stimulus base career cell injury chemotherapeutic agent clinical application deafness dosage drug development drug discovery genetic manipulation hearing impairment in vivo in vivo Model inhibitor/antagonist lateral line microbial novel novel therapeutics ototoxicity ototoxin prevent protective effect public health relevance receptor relating to nervous system research study response screening socioeconomics sound systems research

项目摘要

DESCRIPTION (provided by applicant): Millions of people in the U.S. suffer from hearing loss caused by permanent damage to sensory hair cells of the inner ear. Hair cell damage often results from exposure to excessive sound or particular licit drugs, such as the aminoglycoside antibiotics. The overall goal of this proposed research is to discover novel drugs that prevent aminoglycoside-induced hair cell death and preserve hearing loss in patients requiring these life-saving antibiotics. For this work we will use the zebrafish lateral line, which is a powerful n vivo model for studying mechanisms of hair cell death and protection. Our preliminary data indicate that caffeine significantly protects hair cells from aminoglycoside damage. The specific goal of this research is to determine the mechanism by which caffeine confers protection, and to identify additional natural products that prevent aminoglycoside-induced hair cell death. This project has two specific aims: 1) Test the hypothesis that caffeine otoprotection is mediated by inhibition of p53 and adenosine signaling, and 2) Test the hypothesis that natural products are novel agents for preventing aminoglycoside ototoxicity. Our previous research demonstrates that aminoglycosides activate p53 in damaged hair cells. Caffeine is a known p53 inhibitor, in part via its interaction with adenosine signaling. For Aim 1, we will use pharmacologic and genetic manipulation to modulate p53 and adenosine receptors during aminoglycoside treatment. Caffeine is a plant alkaloid and other natural products, including plant and microbial extracts, likely represent an untapped source of novel otoprotective agents. In Aim 2, we will conduct a series of drug discovery experiments to identify natural products that act as hair cell protectants and to characterize their mechanisms of action. These studies will provide new lead compounds for auditory drug development. By specifically targeting caffeine, a widely used compound with a well-characterized safety profile, we increase the likelihood that our findings may be quickly translated into clinical application. Student researchers are integral to all aspect of this project. Students will learn cutting- edge cell biology and drug discovery techniques that will bolster their biomedical career opportunities, while actively contributing to the discovery of new compounds that prevent drug-induced hearing loss.

描述（由申请人提供）：美国有数百万人因内耳感觉毛细胞永久性损伤而遭受听力损失。毛细胞损伤通常是由于接触过多的声音或特定的合法药物（例如氨基糖苷类抗生素）造成的。这项拟议研究的总体目标是发现新的药物，以防止氨基糖苷类药物引起的毛细胞死亡，并保护需要这些救命抗生素的患者的听力损失。在这项工作中，我们将使用斑马鱼侧线，它是研究毛细胞死亡和保护机制的强大体内模型。我们的初步数据表明，咖啡因可显着保护毛细胞免受氨基糖苷类药物的损伤。这项研究的具体目标是确定咖啡因提供保护的机制，并确定其他可防止氨基糖苷类诱导的毛细胞死亡的天然产物。该项目有两个具体目标：1) 检验咖啡因耳保护作用是通过抑制 p53 和腺苷信号传导介导的假设，2) 检验天然产物是预防氨基糖苷类耳毒性的新型药物的假设。我们之前的研究表明，氨基糖苷类药物可以激活受损毛细胞中的 p53。咖啡因是一种已知的 p53 抑制剂，部分是通过其与腺苷信号传导的相互作用实现的。对于目标 1，我们将在氨基糖苷类治疗期间使用药理学和基因操作来调节 p53 和腺苷受体。咖啡因是一种植物生物碱和其他天然产物，包括植物和微生物提取物，可能代表了新型耳保护剂的未开发来源。在目标 2 中，我们将进行一系列药物发现实验，以确定可作为毛细胞保护剂的天然产物，并表征其作用机制。这些研究将为听觉药物的开发提供新的先导化合物。通过专门针对咖啡因（一种广泛使用且具有良好安全性的化合物），我们增加了将我们的发现快速转化为临床应用的可能性。学生研究人员是该项目各个方面不可或缺的一部分。学生将学习尖端的细胞生物学和药物发现技术，这将增加他们的生物医学职业机会，同时积极为发现做出贡献预防药物引起的听力损失的新化合物。