Investigating the origin and functional properties of immune cells in noise-induced hearing loss

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PROJECT SUMMARY/ABSTRACT In this proposed work, we seek to understand the cellular identity of macrophages, the main immune cells in the cochlea, in noise-induced hearing loss (NIHL). Our previous studies have shown that macrophages in the brain have different developmental origins and their origin is associated with differences in their cellular identity and functions depending on each disease condition. At present, the cellular identities and functional properties of macrophages after noise damage are not well understood. Combining macrophage fate-mapping analysis with single-cell RNA sequencing, our preliminary data revealed that cochlea macrophages during embryonic development and in healthy adult are from two distinct origins. In-depth transcriptional analysis of cochlea macrophages at single-cell resolution in steady state demonstrated the presence of several transcriptionally distinct clusters of macrophages with specific biological functions. Based on this data and our previous work on brain macrophages, we hypothesize that macrophages from different origins are involved in NIHL depending on the age of the animal and stage of the disease (acute, recovery or recovered). Their distinct developmental origin results in transcriptional diversity and differential responses to noise damage. Our findings will contribute to the understanding of cochlea macrophage heterogeneity and functions in relation to their ontogeny after noise damage. Defining the origins and differential gene expression and functions of cochlea macrophage populations will help us to refine our understanding of the role of these cells in different stage after noise damage and enable us to design new molecular and cellular therapies based on targeting inflammation. Specific Aim 1: Identifying the cellular origin of cochlea macrophages in young adult and aged mice exposed to noise damage. Specific Aim 2: Identifying mechanisms by which macrophages contribute to NIHL through single-cell RNA sequencing of macrophage populations present in cochlea.