Area:
Inner ear, hair cells, actin cytoskeleton, ion channels, mechanotransduction
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High-probability grants
According to our matching algorithm, Uri Manor is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2020 — 2021 |
Coleman, Todd P (co-PI) [⬀] Kyriakakis, Phillip Manor, Uri |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
A Novel Model System For Restoring Hearing in Vivo @ Salk Institute For Biological Studies
Project Summary/Abstract Approximately 1 out of 400 children are born with significant hearing loss, making congenital deafness one of the most common disorders affecting young children. Approximately 50% of congenital deafness is genetic in origin. Currently, the only available treatments for hearing loss are cochlear implants or hearing amplification. While these treatments are often life-changing, they are limited in their ability to restore hearing to normal, which results in lifelong struggles beginning acutely in childhood. Gene therapy approaches for treating recessive hearing loss presents a challenging but exciting opportunity. Viral delivery of functional genes to the ear is challenging, especially in mice ? current in vivo viral delivery methods only transduce a fraction of the sensory hair cells necessary for proper hearing function, and only works easily for smaller proteins. Moreover, multiple applications of viral vectors may be required to target the optimal timing and duration for therapy. Mice and humans lacking the actin-regulatory protein Eps8 are deaf, and Eps8 KO mice have very short stereocilia that fail to contact the tectorial membrane in the organ of Corti. A novel transgenic mouse line will be generated to study the potential of postnatal gene expression in a deaf Eps8 KO mouse model. Using the PhyB system, a mouse line will be created wherein any UAS controlled transgene?s expression can be activated with red light or inactivated with far-red light. Using this system, UAS-Eps8 expression in vivo will be induced by either red light or doxycycline. Systematically varying the initiation and duration of Eps8 expression, then testing for hearing function and stereocilia elongation will facilitate the restoration potential of stereocilia elongation and hearing restoration in vivo in postnatal mice. Furthermore, the role of Eps8 in both development and maintenance of stereocilia over the lifetime of the organism will be elucidated in future studies. Overall, this proposal will pave the way for many future projects probing the effects of gene expression modulation in vivo and will provide an innovative but practical model system for probing and expanding the critical period for hearing restoration.
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0.922 |