Irina Calin-Jageman, Ph.D.
The Research
Emory University
Harmonin interactions with voltage-gated Ca3+ channels in a mouse model of Usher syndrome
Usher syndrome is the leading cause of hereditary deafness and combined deafness and blindness in humans. This research will illuminate a novel mechanism of Ca3+ channel regulation that may be important for auditory function. By carefully characterizing the defects in Ca3+ channel properties in the mouse Usher syndrome model, the researcher will be able to follow-up with strategies to restore function to these mice, which may be ultimately useful in limiting deafness and balance problems in human patients of Usher syndrome.
Cortical synaptic plasticity in a mouse model of moderate sensorineural hearing loss
Usher syndrome is the leading cause of hereditary deafness and of combined deafness and blindness. The most severe form of the disease, Usher syndrome type 1 (USH1), has been linked to mutations in genes encoding myosin VIIa, cadherin 23, protocadherin 15, sans and harmonin. These USH1 proteins are localized in hair cells, which are the specialized sensory cells of the cochlea. A prevailing hypothesis is that USH1 proteins may participate in a macromolecular complex necessary for signal transduction and development of cochlear morphology. A key member of this complex is harmonin (USH1C), a protein containing PDZ domains, which are motifs mediating protein-protein interactions in a wide variety of molecules. Harmonin, via direct interactions with other USH1 proteins, may serve as a molecular scaffold for organizing critical signaling molecules in hair cells. Therefore, clues to understanding how genetic alterations in harmonin cause Usher’s syndrome may be revealed in analyses of its protein-protein interactions. We have characterized a novel interaction between harmonin and Ca√1.3 (L-type) Ca2+ channels, the primary voltage-gated Ca2+ channels in hair cells. Preliminary data indicate that harmonin directly interacts with Ca√1.3 , and that these two proteins may be colocalized in the apical membrane of cochlear hair cells. Given the importance of PDZ domain-containing proteins for targeting and clustering ion channels, the proposed research will test the hypothesis that the interaction between harmonin and Ca√1.3 is essential for the proper targeting and localization of apical Ca√1.3 channels in cochlear hair cells. That genetic disruption of the genes encoding Ca√1.3 and harmonin independently lead to deafness in mice provides compelling rationale for the proposed research. The specific aims are to further characterize this interaction between Ca√1.3 and harmonin utilizing biochemical and immunocytochemical techniques. A major goal is to develop a theoretical and experimental foundation on which to build an independent research plan focusing on the molecular and genetic alterations that can lead to cochlear dysfunction and hearing impairment.