A Multi-omics Investigation of Incident Persistent Tinnitus

持续性耳鸣事件的多组学研究

• 批准号: 10705763
• 负责人: Oana Alina Zeleznik
• 金额: $ 22.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705763
• 关键词: Address; Age; American; Analgesics; Biological Markers; Caffeine; Canada; Candidate Disease Gene; Cholesterol Esters; Cognition; Data; Data Collection; Databases; Development; Disease; Economic Burden; Enrollment; Environmental Exposure; Environmental Risk Factor; Enzymes; Etiology; Female; Frustration; Future; Genetic; Genetic Variation; Genetic study; Genomics; Germ-Line Mutation; Goals; Health Care Costs; Hearing; Hearing problem; Individual; Intake; Intervention; Investigation; Knowledge; Lecithin; Logistic Regressions; Longevity; Longitudinal cohort; Longitudinal cohort study; Lysophosphatidylcholines; Mental Health; Meta-Analysis; Metabolic Pathway; Metabolism; Mission; National Institute on Deafness and Other Communication Disorders; Nurses' Health Study; Outcome; Participant; Pathway interactions; Phosphatidylethanolamine; Plasma; Plasmalogens; Population Heterogeneity; Prevention strategy; Productivity; Public Health; Publishing; Quality of life; Questionnaires; Research; Research Personnel; Resources; Risk; Risk Factors; Sleep disturbances; Tinnitus; Triglycerides; United States National Institutes of Health; Update; Veterans; Woman; biobank; career; cohort; daily functioning; disability; drug metabolism; economic impact; effective therapy; epidemiologic data; ethnic minority; evidence base; experience; follow-up; gene environment interaction; genetic variant; genome wide association study; genomic data; high risk; homocitrulline; improved; innovation; male; member; men; metabolomics; modifiable risk; multiple omics; neuroprotection; novel; offspring; population based; prevent; racial minority; secondary analysis; therapeutic target; treatment strategy

ABSTRACT Over 50 million Americans experience tinnitus. Persistent tinnitus can cause considerable suffering and disability, impairing sleep, cognition, mental health and daily function, and the economic burden due to disability, lost productivity and healthcare costs is substantial. However, little is known about the precipitants and pathways that lead to persistent tinnitus and treatment options are limited. Our long-term goal is to identify treatment targets and preventative strategies to reduce tinnitus burden and improve quality of life. Our overall objectives are to (i) identify novel metabolomic and multi-omic risk factors for the development of tinnitus among two large longitudinal cohorts of women (N>26,000); and (ii) collect tinnitus-related individual level data in two additional ongoing cohorts of younger and more diverse men and women (N>70,000). Our central hypotheses are that specific plasma metabolites are associated with risk of developing tinnitus and that genetic variants influence how environmental exposures contribute to the development of tinnitus. The rationale is that identifying risk factors for tinnitus will provide a strong scientific framework for improving tinnitus management, and expanding data collection to include younger individuals will create a comprehensive resource that will enable studies of genetic and environmental factors and will be invaluable in advancing future tinnitus research. The study objectives will be addressed in three specific aims: 1) Identify plasma metabolomic risk factors for developing persistent tinnitus; 2) Evaluate genomics and gene-environment interactions as risk factors for developing persistent tinnitus; and 3) Collect tinnitus information in two ongoing cohorts of younger individuals. We will leverage rich assets from four longitudinal cohort studies and findings from two large tinnitus genome-wide association studies (GWAS). In Aim 1, we will use logistic regression to identify novel metabolomic risk factors for developing tinnitus. In Aim 2a, we will conduct a GWAS and perform a meta- analysis with published tinnitus GWAS results from the UK Biobank. In Aim 2b, we will assess how genetic variations in enzymes responsible for caffeine and analgesic metabolism modulate associations between caffeine intake or analgesic use and tinnitus risk. In Aim 3, we will leverage regularly administered questionnaires in 2 well-characterized younger cohorts to collect detailed tinnitus information. This innovative proposal integrates omics with epidemiological data to identify new risk factors for tinnitus, improve understanding of tinnitus etiology and reveal metabolic pathways and candidate genes for future functional follow-up. The proposed research is significant because identifying risk factors and omics precursors may enable earlier neuroprotective interventions when treatments are more likely to be effective. As an early-stage investigator, this project will provide me with necessary preliminary data for a future R01 proposal to extend these large-scale multi-omics investigations of tinnitus, identify additional novel risk factors, and uncover new treatment targets in women and men across the lifespan, and advance my career to the next stage.

抽象的 超过5000万美国人经历了耳鸣。持续的耳鸣会造成巨大的痛苦，并且 残疾，睡眠障碍，认知，心理健康和日常功能以及由于 残疾，生产力失去和医疗保健成本是巨大的。但是，关于降水剂知之甚少 导致持续性耳鸣和治疗选择的途径受到限制。我们的长期目标是确定 治疗目标和预防策略减轻耳鸣负担并改善生活质量。我们的整体 目的是（i）确定发育发育的新型代谢组和多摩变风险因素 在两个妇女的大型纵向人群中（n> 26,000）； （ii）收集与耳鸣相关的个人级别数据 在另外两个持续的年轻男女同伙中（n> 70,000）。我们的中心 假设是特定的血浆代谢产物与发育nit含耳鸣的风险有关，遗传 变体会影响环境暴露如何有助于耳鸣的发展。理由是 确定耳鸣的危险因素将为改善耳鸣管理提供一个强大的科学框架， 扩大数据收集到包括年轻人的数据将创建一个全面的资源 启用对遗传和环境因素的研究，并且在推进未来的耳鸣方面将是无价的 研究。研究目标将以三个具体目的解决：1）确定血浆代谢组风险 发展持续性耳鸣的因素； 2）评估基因组学和基因环境相互作用作为风险 发展持续性耳鸣的因素； 3）收集两个正在进行的年轻人群中的耳鸣信息 个人。我们将利用来自两个大型纵向队列研究和发现的丰富资产 耳鸣全基因组关联研究（GWAS）。在AIM 1中，我们将使用逻辑回归来识别新颖 发育耳鸣的代谢组危险因素。在AIM 2A中，我们将进行GWAS并执行元 通过英国生物库的发表的Tinnitus GWAS的分析结果。在AIM 2B中，我们将评估遗传 负责咖啡因和镇痛代谢的酶的变化调节了关联 咖啡因摄入量或止痛药和耳鸣风险。在AIM 3中，我们将利用定期管理 2个特征良好的年轻同伙中的问卷调查，以收集详细的耳鸣信息。这种创新 提案将OMICS与流行病学数据集成在一起，以确定耳鸣的新风险因素，改善 了解耳鸣病因并揭示未来功能的代谢途径和候选基因 后续。拟议的研究很重要，因为识别危险因素和OMIC前体可能 当治疗更有可能有效时，可以实现早期的神经保护干预措施。作为早期 调查员，该项目将为我提供必要的初步数据，以供未来的R01提案扩展 这些大规模的多摩学调查耳鸣，确定其他新型风险因素，并发现了新的 整个生命周期的男女的治疗目标，并将我的职业生涯推向下一阶段。