Project Summary For the first phase of our CoBRE award, we are aiming to develop infrastructure and expertise base, as well as to build a critical mass of funded investigators for translational auditory and vestibular research. Towards these goals, three groups led by Drs. Litao Tao, Justine Renauld, and Jun Xia respectively, will collaborate to conduct a preliminary study of Ménière’s Disease, one debilitating disease affecting millions of people. Ménière’s Disease (MD), characterized by fluctuating hearing loss and vertigo, is a poorly understood disease for which the etiology is still unknown. While the pathophysiology of MD remains to be discovered, it is believed that this disorder arises from endolymph homeostasis imbalance. Endolymphatic hydrops, an enlargement of the membranous labyrinth in the inner ear, is a hallmark of the disease. To gain better understanding of this complex disease, this collaborative effort aims to look at 3 synergic ways to uncover the development of MD and endolymphatic hydrops. In this project, we will (1) Identify and validate genetic variants associated with MD from the whole genome sequencing data of more than 1300 patients suffering from MD; (2) characterize the transcriptional changes of an endolymphatic hydrops mouse model’s lateral wall, which is essential for endolymph production and regulation; and (3) identify the distal enhancers by epigenetic study to correlate potential non-coding hot spots from the genetic variant highlighted in Aim 1 with the functional genes affected in the lateral wall discovered in Aim 2. We believe this project with multiple approaches will not only provide new insight into the pathogenesis of MD, but also improve our understanding of lateral wall function and regulation which will have a significant impact for the development of future targeted treatments for MD therapy but also other strial disorders. This supplemental award project aligns with the goal of our CoBRE award. Through collaborations, three teams can learn from each other and will gain new expertise together for studies of strial functions and disorders. Results from this preliminary study will lay the foundation to further investigate the molecular mechanisms of MD and to explore potential treatment options. As junior faculties, Drs. Tao, Renauld and Xia will seek funding through NIH or private foundations to support their future studies on MD.