The overall goal of the project is to define and characterize the organelles and specialized molecular machinery for protein assembly, processing and transport in hair cells, and the defects in this process that cause deafness. We propose here to investigate the mechanisms by which TOMT regulates transport of a subset of functionally important proteins in hair cells, and to begin to uncover TOMT-associated proteins that participate. Based on our preliminary data, we hypothesize that TOMT is an endoplasmic reticulum protein that is critical for assembly and transport of a specific set of transmembrane proteins in hair cells. To test our hypothesis, we will: i) use immunolocalization and immunogold transmission electron microscopy to precisely localize TOMT to hair-cell specific transport organelles; ii) identify and characterize important TOMT functional domains; and iii) look for interaction partners for TOMT that functionally cooperate in hair cell protein transport. Our preliminary data show the feasibility of our approach. We anticipate that our studies will elucidate new insights into the unique molecular machinery of hair cell protein transport that establishes distinctive functional specializations critical for auditory processing. Furthermore, a better understanding of protein transport mechanisms in hair cells has the potential to provide important context for protein transport deficits that are common in hearing loss.
Hearing loss is a major health problem that significantly affects the life quality of affected individuals. Several forms of hearing loss involve deficits in protein transport pathways in cochlear hair cells, including those caused by mutations in TOMT/LRTOMT2. For this project we will investigate the function of Tomt in protein transport in hair cells. We anticipate providing new leads for the development of therapeutic approaches for the treatment of some forms of hearing loss.
