Emory University
The essential role of URB, a novel secreted protein, in cochlear development and planar cell polarity signaling

Hearing depends on highly structured hair bundles in the cochlea properly oriented towards the lateral border of the cochlear duct. Abnormalities in this hair bundle structure or its orientation results in hearing loss, for example in the hereditary disorder Usher syndrome. However, the molecular mechanisms that build the polarized structure of individual hair cells remain poorly understood. Our research focuses on the role of a novel secreted protein, URB, in hair bundle morphogenesis and cochlear development. In particular, we are testing whether URB functions as part of a Planar Cell Polarity (PCP) signaling pathway, a highly conserved pathway of widespread biological interest. We are also investigating possible links between URB and the Usher syndrome network of proteins. We hope that defining these roles for URB in bundle morphogenesis will help in the design of rational therapies for the treatment of Usher syndrome and other forms of hereditary hearing loss in the future.

Oregon Health & Science University
Characterization of Usher syndrome 1F protein complexes

Much of our current knowledge on the molecular makeup of the hair bundle has origins in genetic studies. Several key genes have been discovered but are limited to those genes that are absolutely required for hearing and dispensable in other systems. Many independent genetic mutations also occur in a handful of genes, so that finding new genes can be quite difficult and expensive. My colleague Peter Barr-Gillespie, Ph.D., has pioneered the use of hair bundle isolation techniques to allow studies of the hair bundle proteome, allowing us to uncover many of the features of the hair bundle in single experiments. The next step is to look at how these proteins interact to fulfill the functions of a mechanically sensitive hair bundle and the effects of genetic abnormalities on the whole bundle proteome (set of proteins). In this project I will analyze individual protein complexes using a new hair bundle isolation strategy that allows us to isolate and analyze protein complexes from the hair bundle. I will perform a comparative analysis of the makeup of all Usher syndrome protein complexes. This will shed new light on the proteins involved directly in mechanotransduction.

University of Vermont and State Agricultural College
The Role of a Mutation in Histidyl-tRNA Synthetase in Usher-like Syndrome Deafness

An Usher-like syndrome, comprising deafness, blindness, and fever-induced hallucinations was recently discovered, caused by recessive inheritance of a mutation in histidyl-tRNA synthetase (HARS). The HARS enzyme is required for protein production in cells: it attaches the amino acid histidine to a transfer ribonucleic acid (RNA) molecule which activates and transports the amino acid to the ribosome for protein synthesis. We will measure the effects of this mutation on the molecules required for protein synthesis. Preliminary results suggest HARS may be chemically modified by the cell, and that mutant HARS is modified differently, which is evidence HARS may have roles in the cell separate from its known function in protein synthesis. We additionally propose to determine the interactions of HARS and mutant HARS with other cellular proteins, specifically in cells derived from embryonic mouse inner ears, as a first step in elucidating a different role for HARS in hearing.

Research area: Usher and Usher-like syndrome deafness

Long-term goal of research: Our long term goal is to describe the specific role HARS, and the HARS mutation, plays in sensory cell development and maintenance. With a greater understanding of the proteome - the expressed proteins and protein interactions of a cell - during different stages of development of affected cells, we hope to discover more potential avenues for therapy to prevent or alleviate symptoms of Usher and Usher-like syndromes.

University of Utah
Understanding the function of PDZD7 in hair cells

Usher syndrome is a devastating genetic disease affecting both hearing and vision. It is the leading genetic cause of combined deafness and blindness in the world. Usher syndrome is clinically and genetically heterozygous. It is classified into three clinical types according to the severity of hearing and vestibular symptoms. Zou's studies focus on type 2, which is the dominant form of Usher syndrome and characterized by congenital moderate degree of hearing loss, normal vestibular function, and retinitis pigmentosa. PDZD7 was recently reported to exacerbate the symptoms and contribute the digenic form of Usher syndrome type 2 when patients carry heterozygous PDZD7 mutations. Zou has successfully generated a Pdzd7 knockout mouse. Using this animal model, Zou plans to investigate the function of PDZD7 during hair bundle development in the cochlea. This study will be significant for the future diagnosis and treatments for Usher syndrome type 2.