Multi-Omic and Functional Analyses for Hearing Preservation and Restoration

National Institute On Deafness And Other Communication Disorders

Investigators

Linked publications & trials

Abstract

The section on omics and translational science of hearing, within the Neurotology Branch (NOB), is dedicated to investigating the coordinated regulation of gene expression across the diverse cell types of the inner ear in health and disease. 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. Our secondary objective is to advance multi-omic and clinical data sharing in the field of hearing research. 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 and clinical data: We have developed the gene Expression Analysis Resource (umgear.org), a comprehensive platform for the visualization, analysis, and sharing of multi-omic data. More recently we work along side the AVCRS to support the development of a new tool for clinical data sharing in the field. Our laboratory moved from the University of Maryland School of Medicine to the National Institute on Deafness and Other Communication Disorders, in February 2023. In the past two years our efforts ranged from relocation to setting up existing projects and protocols, to new project development with an emphasis on uniquely intramural type projects. 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 found a critical role for the RFX transcription factors in vestibular hair cell development 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. Finally, for the POU3F4 transcription factor, using multi-omic analyses, we were able to demonstrate a key pathway regulated by POU3F4 that is critical to forming the cochlear modiolar bone. 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. We studied a possible role for Raloxifene – an FDA approved selective estrogen receptor modulator (SERM) in otoprotection from noise exposure. We worked towards developing a model for screening drugs for age related hearing loss and formed an intramural group of investigators that will be working in collaboration to test specific estrogen receptor modulators with their multi-system effect on a mouse model for post-menopausal women. Finally, we initiated a study, as part of the Neurotology Branch, to identify physiological as well as molecular markers for inner ear injury. Tools for Sharing, Visualization, and Analyzing Multi-Omic Data: We advanced the development of the gEAR portal, reaching over 2349 registered users and 1193 datasets. In July 2024 we launched gEAR 2.0, which was the product of collaborating with a user-interface/user-experience group from the University of Maryland College Park. This new version was designed based on user-feedback and aims to simplify the user experience. We made numerous enhancements to the platform including improvements to the projection tool, and support for spatial transcriptomics data. Through workshops during the Association for Research in Otolaryngology Midwinter meeting, and the EARssentials course, 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. Finally, this year we advanced efforts for designing tools for clinical data sharing. This project is done as part of the HearShare consortium and in collaboration with our Auditory and Vestibular Clinical Research Section of the Neurotology Branch. 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.