Genomic investigations of the auditory system

听觉系统的基因组研究

• 批准号: RGPIN-2022-04500
• 负责人: Drögemöller, Britt
• 金额: $ 2.7万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744192
• 关键词: Genomic; investigations; auditory; system

Background: The way in which we interpret the world is influenced by our ability to process sound. This fundamental process involves complex systems in the auditory system, with genetic factors playing an important role in controlling the normal functioning of the inner ear. However, investigation of these factors has been hampered by challenges associated with accurately characterizing hearing in large population cohorts and capturing gene expression profiles in the diverse inner ear cells. Further, while it is known that there are differences in the way in which males and females perceive sound, and more than one-third of genes exhibit sex-biased differences in gene expression in specific tissues, there are gaps in our understanding of the genomic and biological mechanisms underlying these differences. Objectives: The long-term objective of my research program is to use genomics to understand the biological pathways underlying hearing. The short-term objectives for my program are to: (i) Uncover novel genes and pathways involved in hearing in humans; and (ii) Identify sex-specific differences in murine cochlear gene expression profiles. Methods: To identify biological pathways that are important for hearing, we will use machine learning algorithms to classify individuals from the healthy elderly population according to their variability in hearing. We will use these data to perform genomic analyses to identify genetic variants and genes that are associated with these distinct patterns of hearing. Once these genes have been identified, we will use single cell RNA sequencing data to investigate the expression patterns of these genes. These data will provide information relating to the unique expression patterns that are associated with genes that are involved in different hearing processes. These distinct gene expression signatures can in turn be used to identify additional genes that display similar expression patterns and are thus likely to also be involved in hearing. We will build on these analyses to investigate sex-specific differences in gene expression patterns observed in murine inner ear cells. These data will substantially add to our knowledge regarding the pathways that are important to hearing, and importantly, how these pathways change during the aging process in both sexes. Impact: The data generated from this program will address key gaps in knowledge regarding the genomic pathways involved in sex- and age- related variability in hearing. These data will pave the way for future research, which through additional omics analyses and evolutionary comparisons, will improve our understanding of the complex biological mechanisms that underlie hearing. This discovery grant will provide training opportunities in computational and molecular biology for three graduate students and two undergraduate students. The incorporation of state-of-the art techniques and analyses will open diverse career opportunities in the natural sciences.

背景：我们解释世界的方式受到我们处理声音的能力的影响。这一基本过程涉及到听觉系统中的复杂系统，遗传因素在控制内耳的正常功能方面发挥着重要作用。然而，这些因素的研究一直受到与准确描述大人群队列中的听力特征和捕获不同内耳细胞中的基因表达谱相关的挑战的阻碍。此外，尽管已知男性和女性感知声音的方式存在差异，超过三分之一的基因在特定组织中的基因表达存在性别偏见的差异，但我们对这些差异背后的基因组和生物学机制的理解存在差距。目的：我的研究计划的长期目标是利用基因组学来了解听力的生物学途径。我的计划的短期目标是：(I)发现与人类听力有关的新基因和途径；以及(Ii)识别小鼠耳蜗基因表达谱中的性别差异。方法：为了识别对听力有重要影响的生物途径，我们将使用机器学习算法，根据听力的变异性从健康老年人群中对个体进行分类。我们将使用这些数据进行基因组分析，以确定与这些不同的听力模式相关的遗传变异和基因。一旦确定了这些基因，我们将使用单细胞RNA测序数据来研究这些基因的表达模式。这些数据将提供与参与不同听力过程的基因相关的独特表达模式的信息。这些不同的基因表达特征反过来可以用来识别表现出相似表达模式的其他基因，因此很可能也与听力有关。我们将在这些分析的基础上，研究在小鼠内耳细胞中观察到的基因表达模式的性别差异。这些数据将大大增加我们对听力重要途径的了解，更重要的是，这些途径在男女衰老过程中如何变化。影响：该计划产生的数据将解决有关与性别和年龄相关的听力变异所涉及的基因组途径方面的关键知识空白。这些数据将为未来的研究铺平道路，通过额外的组学分析和进化比较，将提高我们对构成听力基础的复杂生物学机制的理解。这笔发现基金将为三名研究生和两名本科生提供计算和分子生物学方面的培训机会。结合最先进的技术和分析将在自然科学领域开辟不同的职业机会。