An Assay to Screen for Drugs Against Transmembrane Proteins Associated with Deafness

Georgia Institute Of Technology, Atlanta GA

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Abstract

Project summary: Transmembrane channel proteins are putative mechanotransducers in the hair cells of cochlea in human; mutations in these proteins are linked to human deafness. Currently models for these disorders are either expensive low-throughput animal models that are not amenable to high-throughput screening, or cell-culture based models that do not necessarily mimic the proper physiology in human or give relevant readout. The freely living nematode C. elegans is an excellent genetic model system that can be used to heterologously express proteins and study their functions in an in vivo environment. Our previous work showed that the C. elegans Tmc homologs are expressed in sensory neurons; thus expressing wildtype or mutant mouse or human TMCs in C. elegans neurons could potentially be used as a platform for studying TMCs functions and to perform drug screens against TMC functions. Another current bottlenecks for this problem is that calcium imaging upon mechanical stimulation to the animals is extremely manual and low throughput. The objective of this project is to establish a technology and assay platform for screening functions of mammalian transmembrane channel proteins in vivo, and to use this system to perform pilot drug screens as a proof of concept and potentially identifying drug candidates. This project is innovative because it is the first time high-throughput screens can be performed on mechanobiology in vivo. It is significant on both technological and scientific grounds: this system will allow studies of function and dysfunction of TMCs and other related channel proteins in vivo, and this knowledge as well as compounds yielded from the screen may have direct relevance to clinical applications in treating deafness related to TMCs in cochlear impairment.