Molecular and physiologic architecture of the human inner ear

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

PROJECT SUMMARY: The Centers for Disease Control in the US reports that more than 15% of adults over the age of 18 suffer from hearing loss, making it the third most prevalent chronic disease, more common than diabetes or cancer1. While hearing aids and cochlear implants are available, they do not always provide benefit to patients, and they fail to reverse the underlying pathology of hair cell loss. Much of what is known about the inner ear’s molecular architecture is based on animal models. Key unanswered questions remain about the genetic architecture and molecular mechanisms of transcriptional control within the adult human inner ear. Unlike any other organ in the body, the human inner ear cannot be biopsied in living individuals without making the organ completely non-functional. While there are established temporal bone laboratories throughout the US focused primarily on temporal bone histopathology, there remains a large gap in access to living inner ear samples. In this proposal, we have established a collaborative team of surgeons, scientists, and surgeon- scientists to create a molecular and physiologic biorepository of the human inner ear at unprecedented scale. This will include primarily inner ear tissues that are comprised of the cochlea and the vestibular apparatus. We will also collect non-invasive physiologic data such as otoacoustic emissions. The purpose of the study is to identify the normal physiology and molecular architecture of the human inner ear. Our ultimate goal is to determine whether what we know about mammalian inner ears from animal models is true in humans and identify potential therapeutic targets for patients with hearing loss and vestibular disorders. Specific Aim 1: Establish pipeline of human vestibular epithelia for in vitro modeling. We will establish a pipeline from the operating room to the laboratory to collect utricles, saccules, and ampullae. Two sources will be utilized: patients undergoing ablative therapies of the inner ear and lateral skull base, and organ donor tissues. Our experiments will consist of histology, single cell transcriptomics, spatial transcriptomics, and in vitro cultures for perturbations. Specific Aim 2: Characterize the physiologic and molecular composition of the human cochlea. The adult human cochlea remains one of the most inaccessible organs. While there are many samples in the archives of established temporal bone laboratories comparing audiometry and histopathology, to the best of our knowledge, there is currently no direct physiologic and molecular measure of the human cochlea. We aim to establish a pipeline for performing otoacoustic emissions on organ donors followed by harvesting the cochlea. Histologic, single cell transcriptomic, and spatial transcriptomic characterization of the cochlea will be directly correlated with physiologic measurements. By creating a biorepository of human inner ear tissues, this project will enable a range of studies that can dramatically advance our understanding of the molecular mechanisms at work in the adult human inner ear.