Multi-Omic and Functional Analyses for Hearing Preservation and Restoration

我们的实验室位于神经病学分部，致力于研究内耳不同细胞类型的基因表达的协调调节。我们的主要目标是理解控制内耳发育和功能的分子程序，最终努力开创遗传性和获得性听力损失的新疗法。我们的合作努力涵盖了广泛的领域，从遗传学和功能基因组学到成像和听力/平衡生理学。我们采用了一系列不同的体外和体内模型。除了我们的创新研究追求，我们也非常重视培养下一代科学家和临床医生-科学家。 以下概述了推动我们工作的三个主要重点领域： 内耳发育中的细胞类型特定分子通路：我们的专长在于识别对内耳发育和功能至关重要的转录因子和基因调控网络。通过这种探索，我们揭示了对听力恢复至关重要的新基因和新途径。 听力的性别差异和获得性听力损失的分子基础：我们的研究旨在破译性别之间在听力生理学和对噪音易感性方面的根本差异。我们的目标是为潜在的治疗干预铺平道路。 用于共享、可视化和分析多组数据的工具：我们开发了基因表达分析资源(umgear.org)，这是一个用于可视化、分析和共享多组数据的综合平台。 今年对我们的实验室来说是一个重大的转变，因为我们从马里兰大学医学院搬到了国家耳聋和其他沟通障碍研究所。尽管这一过渡需要付出相当大的努力，包括建立新的实验室、人员配备以及调整和重新建立动物协议，但我们在所有三个方面都继续取得实质性进展。 内耳发育中的细胞类型特异性分子通路：我们在了解RFX下游在前庭毛细胞发育中的分子通路方面取得了进展。我们强调了第1组RFX转录因子在分化和功能中的关键作用。我们的研究还揭示了IKZF2影响外毛细胞发育的信号通路，揭示了它参与分化和维持的过程。值得注意的是，我们的工作展示了四个不同的分子、功能和空间群体在耳廓间充质细胞中的存在。这项研究强调了这种细胞类型的重要性，尽管在发育过程中它的数量很多，但往往没有得到充分的研究，以及它在内耳旁分泌信号中的作用。 听力生理学和预防获得性听力损失的性别差异：我们的研究发现，雌激素信号通路的下游介质对雌性小鼠的耳朵保护至关重要。此外，我们成功地在雄性小鼠身上建立了二甲双胍对噪声引起的听力损失的耳保护作用，在雌性小鼠中观察到了不同的结果。 用于共享、可视化和分析多组数据的工具：我们推进了Gear门户的开发，覆盖了2000多个注册用户和1137个数据集。我们与马里兰大学公园分校的一个用户界面/用户体验小组合作，设计了一个基于用户反馈来修改界面的蓝图。我们引入了分析和可视化工具，包括投影工具，并对工作台进行了实质性的增强。通过在耳鼻喉科研究协会会议期间举办的十多个研讨会，我们帮助用户掌握了该平台。我们致力于保持最新状态，因此我们不断使用最新发布的现场数据集更新平台。 这些成就突显了我们致力于在内耳生物学的理解方面取得开创性进展，最终目标是减轻听力损失的负担。

Our laboratory, situated within the neurotology branch, is dedicated to investigating the coordinated regulation of gene expression across the diverse cell types of the inner ear. Our primary objective is to comprehend the molecular programs governing inner ear development and function, ultimately striving to pioneer new therapies for both genetic and acquired hearing loss. Our collaborative efforts encompass a wide spectrum, ranging from genetics and functional genomics to imaging and hearing/balance physiology. We employ a diverse range of in vitro and in vivo models. In addition to our innovative research pursuits, we also place a strong emphasis on nurturing the next generation of scientists and clinician-scientists. Outlined below are the three key focus areas that drive our work: Cell-Type Specific Molecular Pathways in Inner Ear Development: Our expertise lies in identifying transcription factors and gene regulatory networks pivotal to inner ear development and function. Through this exploration, we unveil novel genes and pathways critical to the restoration of hearing. Sex Differences in Hearing and the Molecular Basis of Acquired Hearing Loss: Our research is geared towards deciphering the fundamental differences in hearing physiology and susceptibility to noise between genders. Our goal is to pave the way for potential therapeutic interventions. Tools for Sharing, Visualizing, and Analyzing Multi-Omic Data: We have developed the gene Expression Analysis Resource (umgear.org), a comprehensive platform for the visualization, analysis, and sharing of multi-omic data. This year marked a significant transition for our laboratory, as we moved from the University of Maryland School of Medicine to the National Institute on Deafness and Other Communication Disorders. Despite the considerable efforts required for this transition, including setting up the new lab, staffing, and adapting and re-establishing animal protocols, we continued to make substantial progress on all three fronts. Cell-Type Specific Molecular Pathways in Inner Ear Development: We made strides in understanding the molecular pathways downstream of RFX in vestibular hair cell development. We highlighted the crucial role of group 1 RFX transcription factors in differentiation and function. Our investigations also unveiled the signaling pathway influenced by IKZF2 in outer hair cell development, shedding light on its involvement in differentiation and maintenance. Notably, our work showcased the presence of four distinct molecular, functional, and spatial populations within otic mesenchyme cells. This research emphasized the significance of this cell type, often understudied despite its abundance during development, and its role in inner ear paracrine signaling. Sex Differences in Hearing Physiology and Prevention of Acquired Hearing Loss: Our studies identified downstream mediators of the estrogen signaling pathway as pivotal for otoprotection in female mice. Moreover, we successfully established Metformin's otoprotective role against noise-induced hearing loss in male mice, with differential outcomes observed in females. Tools for Sharing, Visualization, and Analyzing Multi-Omic Data: We advanced the development of the gEAR portal, reaching over 2000 registered users and 1137 datasets. Collaborating with a user-interface/user-experience group from the University of Maryland College Park, we designed a blueprint to revamp the interface based on user feedback. We introduced analysis and visualization tools, including a projection tool, and made substantial enhancements to the workbench. Through more than ten workshops during the Association for Research in Otolaryngology meetings, we assisted users in mastering the platform. Our commitment to staying current saw us continually update the platform with newly published datasets from the field. These accomplishments underscore our dedication to pioneering advancements in the understanding of inner ear biology, with the ultimate goal of alleviating the burden of hearing loss.