Translational Hearing Center

Project Summary This Center of Biomedical Research Excellence (COBRE) application is to establish the Translational Hearing Center, administered by centrally-located Creighton University, with Boys Town National Research Hospital (BTNRH) and the University of Nebraska Medical Center (UNMC), as institutional partners. Our overall goal is

to build a critical mass of academic translational researchers developing therapeutic intentions to preserve or restore hearing and vestibular function from a wide range of etiologies that cause hearing loss and vestibular deficits. Hearing loss in infants and children results in delayed acquisition of listening and spoken language skills

critical for academic achievement and maximal career trajectories of affected individuals. In the aging population, hearing loss and vestibular deficits without appropriate rehabilitation accelerates aging and cognitive decline. Aim 1: Develop the infrastructure and expertise base for translational auditory and vestibular research

COBRE funding will enable an Administrative Core within the Center to provide a unique, transformational research environment for junior investigators to translate their basic science discoveries into therapeutic strategies that preserve or restore hearing and vestibular function. This will establish a broader nonclinical

research program. The Administrative Core will develop a Drug Discovery and Delivery Core that will coordinate necessary drug screen assays and production of derivatives of lead compounds and their delivery to the inner ear and associated central neural pathways, as well as an Auditory Vestibular Technology Core to validate the

efficacy of lead candidate ototherapeutics hits. Aim 2: Build a critical mass of funded investigators leading translational auditory and vestibular research. We will examine both peripheral and central mechanisms of hearing loss and vestibular dysfunction, and identify pharmacotherapeutic strategies preserve or restore hearing and vestibular function, with multiple

levels of research funding for investigators. We also have an outstanding Mentoring Plan for project leaders, complementing their expertise with senior investigations as Internal Mentors and biostatistical support, as well as outside investigators with translational and clinical expertise as External Mentors. Future plans call for

continued expansion of the Center to include submission of Investigational New Drug applications, safety and efficacy studies and clinical trials in partnership with patient populations served by Creighton University’s academic medical center, Catholic Health Initiatives (CHI) Health system, BTNRH and UNMC.

Individuals with fetal alcohol spectrum disorders (FASD) exhibit impaired auditory processing. The underlying mechanisms for these auditory deficits are unclear. The goal of the proposed research is to model the effects of prenatal alcohol exposure (PAE) in mice to provide foundational insights into neural mechanisms that mediate

auditory processing deficits. Given the important role that parvalbumin (PV) interneurons play in processing of auditory information, it is important to address the impact of PAE on PV interneurons in the primary auditory cortex. It is not known whether altered maturation of PV interneurons contribute to altered inhibition and changes

in the network excitation in the auditory cortex resulting in impairments in auditory processing. Here, we will use a mouse model of maternal voluntary alcohol consumption throughout gestation to examine altered chromatin accessibility in PV interneurons, altered chromatin binding of the pioneer transcription factor Otx2, distribution of

interneuron populations, synaptic connectivity and mechanisms contributing to altered PV interneuron maturation in the primary auditory cortex. The goal of the proposed studies is to provide a molecular basis for the altered auditory processing observed in FASD. We hypothesize that alterations in the PV interneuron

epigenetic modifications could regulate their maturation resulting in altered PV interneuron function that ultimately contribute to auditory processing impairments. These aims bring together labs from vastly different fields to form a team with expertise in PAE neurodevelopment, FASD, chromatin structure, and bioinformatics. Collaboration among these labs enables a

comprehensive approach to study mechanisms that contribute to altered auditory processing in FASD, helping to provide greater insight into the molecular and neural mechanisms of auditory processing. These aims will reveal a chromatin basis for the effects of PAE in the auditory cortex, and identify genomic loci, transcription

factor regulation, and the degree of Otx2 involvement in these alterations that correspond to FASD. Therefore, not only will these findings reveal novel mechanistic insights into PAE, but will also lay the groundwork for future collaboration in the field of chromatin architecture, development of the auditory cortex, and the impact of prenatal

alcohol exposure.