Molecular mechanism in noise-induced hearing loss

噪声性听力损失的分子机制

基本信息

批准号：
10576973
负责人：
Su-Hua Sha
金额：
$ 33.89万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576973
关键词：
Acute Adopted Adult Affect Animal Model Antioxidants Auditory Autophagocytosis Biochemical CaM kinase I activator Calcium Calmodulin Cell Death Cell Nucleus Cell Survival Cells Cessation of life Clinical Clinical Trials Cochlea Cytokine Gene Data Epigenetic Process Event Exposure to FK506 Failure Fluorescent in Situ Hybridization G9a histone methyltransferase Gene Expression Gene Expression Profile Gene set enrichment analysis Genetic Transcription Genomics Goals Hair Cells Health Care Costs Immunohistochemistry Individual Intervention Investigation Measurement Mediating Mediator Metabolic Metabolic Pathway Modeling Molecular Mus Noise Noise-Induced Hearing Loss Nuclear Translocation Outcome Outer Hair Cells Pathologic Pathology Pathway interactions Pharmaceutical Preparations Pharmacological Treatment Phosphotransferases Preparation Presbycusis Prevention Protein Isoforms Quality of life Reactive Oxygen Species Recovery Research Role STK11 gene Sensory Hair Severities Signal Pathway Signal Transduction Small Interfering RNA Surface Synapses System Technology Temporary Threshold Shift Testing Therapeutic Therapeutic Intervention Transfection Virus adeno-associated viral vector attenuation cell injury cytokine design dosage hearing impairment hearing loss treatment in vivo inhibitor inner ear diseases innovation insight mouse model noise exposure novel novel therapeutic intervention nuclear factors of activated T-cells otoprotectant pharmacologic pre-clinical prevent preventive intervention response single-cell RNA sequencing small hairpin RNA tool transcription factor NF-AT c3

项目摘要

ABSTRACT The long-term goals of this research are to elucidate the molecular mechanisms underlying noise-induced hearing loss (NIHL) and to propose rational therapeutic interventions for prevention. Based on our previous findings and consistent with findings in other systems, we will test the hypothesis that prolonged activation of AMPKα (T172) by calcium/calmodulin-dependent kinase kinase 2 (CaMKK2) and liver kinase B1 (LKB1) or reactive oxygen species (ROS) triggers outer hair cell (OHC) death. We further propose that activated CaMKK2 facilitates translocation of nuclear factor of activated T-cells (NFAT) into OHC nuclei, causing release of cytokine genes. Finally, we will use siRNA and pharmacological compounds to block multiple death pathways for potential synergistic protection against NIHL. We will employ a comprehensive experimental approach including in-vivo studies with adult mice to define the underlying molecular mechanisms using short hairpin RNA (shRNA) via virus transfection, single cell RNA-seq (scRNA-seq) with gene set enrichment analysis (GSEA), and fluorescence in-situ hybridization with RNAscope. These studies investigating innovative therapeutic strategies are designed to identify novel avenues for the prevention of NIHL, benefiting the quality of life of affected individuals and reducing healthcare costs. In addition, the data generated by this proposal will make a significant contribution to our understanding of a broad range of inner ear disorders since similarities have been shown in the molecular events associated with noise-induced, drug-induced, and age-related hearing loss.

抽象的这项研究的长期目标是阐明噪声引起的分子机制听力损失（NIHL）并根据我们之前的研究提出合理的治疗干预措施。与其他系统中的发现一致，我们将测试延长激活时间的假设 AMPKα (T172) 通过钙/钙调蛋白依赖性激酶激酶 2 (CaMKK2) 和肝激酶 B1 (LKB1) 或我们进一步提出，活性氧 (ROS) 会触发外毛细胞 (OHC) 死亡。促进活化 T 细胞核因子 (NFAT) 易位至 OHC 细胞核，导致细胞因子释放最后，我们将使用 siRNA 和药理学化合物来阻断潜在的多种死亡途径。我们将采用包括体内在内的综合实验方法。使用短发夹 RNA (shRNA) 对成年小鼠进行研究，以确定潜在的分子机制病毒转染、单细胞 RNA-seq (scRNA-seq) 和基因集富集分析 (GSEA)，以及这些研究探讨了创新的治疗策略。旨在确定预防 NIHL 的新途径，从而提高受影响者的生活质量此外，该提案生成的数据将产生重大影响。有助于我们理解广泛的内耳疾病，因为在与噪声引起的、药物引起的和与年龄相关的听力损失相关的分子事件。