Targeting multiple signaling pathways for tinnitus prevention and treatment

针对耳鸣预防和治疗的多个信号通路

基本信息

批准号：
10197878
负责人：
Jianxin Bao
金额：
$ 120.73万
依托单位：
GATEWAY BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197878
关键词：
Adrenergic alpha-Antagonists Affect Anti-Inflammatory Agents Area Auditory Brain Calcium Channel Calcium Signaling Chemicals China Chronic Clinical Clinical Research Data Development Dose Drug Kinetics Drug usage Ear Exhibits FDA approved Future Generations Goals Health Human Hyperactivity Impairment In Vitro Industry Standard Inflammatory Inflammatory Response Investigational Drugs Investigational New Drug Application Lead Molecular Mus Nervous system structure Noise Induced Tinnitus Noise-Induced Hearing Loss Pathology Pathway interactions Perception Pharmaceutical Preparations Pharmacologic Substance Pharmacology Pharmacology Study Phase Prevention Property Publishing Q-Type Calcium Channels Quality of life Research Research Contracts Safety Salicylic Acids Side Signal Pathway Sleep Small Business Innovation Research Grant Structure-Activity Relationship Subjective Tinnitus T-Type Calcium Channels Testing Time Tinnitus Toxic effect Toxicokinetics Toxicology analog base clinical development cost detection method drug candidate drug development drug metabolism drug repurposing experimental study genotoxicity good laboratory practice hearing impairment in vivo medication safety mouse model negative affect prevent sound

项目摘要

Subjective tinnitus is the perception of a phantom sound, which negatively impacts the quality of life for millions of people worldwide. Despite the great demand for remedy, there are no FDA-approved drugs to prevent or treat tinnitus. Possible causes of tinnitus are complicated. The current view is that hyperactivity in the central auditory nervous system contributes to the majority of tinnitus cases. This abnormal electrical activity, including an increase in delta-band activity, may be the direct result of an increase in T-type calcium channel activity. Other studies suggest that inflammatory responses within the brain may be involved in the development and persistence of tinnitus; therefore, drug candidates targeting both inflammatory and calcium signaling pathways may act synergistically to prevent and treat tinnitus. Tetrandrine (TET), an approved drug used in China, exhibits both anti-inflammatory and calcium channel-blocking properties. Using a new tinnitus detection method in mice, we have shown that both salicylate-induced and noise-induced tinnitus can be effectively treated by TET in a dose-dependent manner. Our hypothesis is that TET or its chemical analogs can be developed as drugs to prevent and treat tinnitus. In our proposed experiments, we have two parallel goals: (1) obtain investigational new drug (IND)-enabling toxicity and pharmacokinetics data for TET (Aim 1) and (2) optimize second-generation products with structure-activity relationship studies of TET and its chemical analogs (Aim 2). Successful accomplishment of Aim 1 will enable TET to advance into clinical development. In addition, the studies of Aim 2 will enable us to identify additional candidates in case TET fails at clinical stages. By targeting multiple cellular signaling pathways that impinge upon tinnitus, our study will open new areas for the treatment and prevention of tinnitus. The extensive body of data publicly available for TET and its analogs will help us significantly reduce development time and costs.

主观耳鸣是对幻音的感知，这会对听觉产生负面影响全球数百万人的生活质量。尽管对补救措施的需求很大，但不是 FDA 批准的预防或治疗耳鸣的药物。耳鸣的可能原因有复杂的。目前的观点是中枢听觉神经系统的过度活跃导致大多数耳鸣病例。这种异常的电活动，包括 δ带活性的增加，可能是T型钙增加的直接结果渠道活动。其他研究表明大脑内的炎症反应可能参与耳鸣的发展和持续；因此，候选药物针对炎症和钙信号通路可能会协同作用预防和治疗耳鸣。中国批准使用的药物粉防己碱（TET）展出具有抗炎和钙通道阻断特性。使用新的耳鸣通过在小鼠中进行检测，我们发现水杨酸盐诱导的和噪音诱导的 TET 可以有效治疗耳鸣，且呈剂量依赖性。我们的假设 TET或其化学类似物可以开发为药物来预防和治疗耳鸣。在我们提出的实验中，我们有两个并行的目标：（1）获得 TET 的研究性新药 (IND) 毒性和药代动力学数据（目标 1)和(2)通过构效关系研究优化第二代产品 TET 及其化学类似物（目标 2）。目标 1 的成功实现将使 TET 进入临床开发。此外，目标 2 的研究将使我们能够以确定其他候选人，以防 TET 在临床阶段失败。通过瞄准多个影响耳鸣的细胞信号通路，我们的研究将为耳鸣开辟新领域耳鸣的治疗和预防。公开可用的大量数据 TET 及其类似物将帮助我们显着减少开发时间和成本。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Detecting Cochlear Synaptopathy Through Curvature Quantification of the Auditory Brainstem Response.

通过听觉脑干反应的曲率量化检测耳蜗突触病。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Bao, Jianxin;Jegede, Segun Light;Hawks, John W;Dade, Bethany;Guan, Qiang;Middaugh, Samantha;Qiu, Ziyu;Levina, Anna;Tsai, Tsung
通讯作者：
Tsai, Tsung

Noise-induced hearing disorders: Clinical and investigational tools.

噪声引起的听力障碍：临床和研究工具。