While 50% of the US population experiences balance problems at some point during their lifetime, there is no currently NIH funded research program focused on gene discovery in the vestibular periphery. Until we know the transcriptome associated with the cell types comprising the vestibular end organs, we will not fully understand the complexity of the system and we will be missing opportunities for drug development to help our children and adults with balance problems. The objective of this research program is to understand the projection of the vestibular efferent neurons to the vestibular periphery in the context of the fundamental molecular sensory organization of the receptors and the vestibular primary afferent neurons. By defining the molecular basis of the efferent/afferent interaction, a clear mechanistic understanding of function will emerge that should provide valuable insight into the causes of disease states associated with balance disorders. This will not only facilitate the development of new drugs to treat our patients with vestibular dysfunction, but will likely lead to the identification of candidate genes and alternatively spliced transcripts that result in vestibular disease. This continuation proposal seeks funding to address four questions that are all focused on providing a functional prediction of the efferent/afferent interaction: 1) What are the genes subserving the efferent/afferent interaction in anatomically and immunohistochemically defined cell types in the vestibular periphery?; 2) Are the muscarinic acetylcholine receptor subtypes 2 and 4 found in the crista ampullaris functional?; 3) Since potassium channels probably are responsible for much of the heterogeneity in afferent and efferent signaling, what are their topographical and cellular locations throughout the vestibular epithelia?; and 4) What are the locations of selected identified proteins and mRNAs subserving the efferent/afferent interaction identified in the previous funding period and during the execution of Aim 1? Once these questions are answered, models for determining the role of the efferent and afferent pathways during vestibular compensation, following vestibular injury, or in specific vestibular disorders such as Meniere's disease or genetic vestibulopathies can be developed. It is likely that completion of these aims will not only provide a clear understanding of the genes responsible for the efferent/afferent interaction, but will benefit other neuroscientists and clinicians who are interested in basic inner ear biology and who work for the benefit of our patients with hearing and balance disorders. [unreadable] [unreadable] [unreadable]