Patricia Loomis, Ph.D. Research Assistant Professor Ph.D., 1994, University of Alabama at Birmingham Room: 2.114 Phone: 847-578-8663 Fax: 847-578-3268 E-mail: patricia.loomis@rosalindfranklin.edu

Although great strides have been made in the study of auditory hair cell stereocilia, the molecular mechanisms controlling the assembly and maintenance of this exquisite example of cytoarchitecture are poorly understood. The Espin family of proteins, which have been implicated in deafness and vestibular dysfunction in humans and mice, are an integral component of this actin cytoskeletal regulatory system. Encoded by a single gene (Espn), the Espins share a C-terminus that is necessary and sufficient for actin bundling activity. While the C-terminus bestows Espins with the classification of actin bundling proteins, the N-terminus, with its diverse functional domains generated by differential start site selection and alternative splicing, imparts upon Espins the recognition as multifunctional actin cytoskeletal regulatory proteins. Which factors are responsible for the regulation of isoform selection and the downstream significance with regard to isoform localization and the ensuing effects on the organization, dynamics and signaling capabilities of bound F-actin during the development and maturation of the inner ear are still unknown. To begin to understand how Espin gene expression is controlled at the level of RNA processing, I am testing the hypothesis that both regulatory sequences on the pre-mRNA and the trans-acting proteins which bind them act in concert to modulate splice site selection in both a mouse and zebra fish model system.

Once severely damaged, human auditory hair cells cannot regenerate. However, gene therapy has the promise of applying genomics-based treatments to aid these cells and possibly restore hearing. Effective application of gene therapy demands that we understand how genes such as Espn are involved in the development of the inner ear and how the proteins encoded by them act in concert to maintain this elaborate cytoarchitecture. Dissection of the processes of alternative splicing of Espin pre-mRNA will further our understanding of how hair cells within the inner ear regulate the complex spatiotemporal patterns of expression of this important family of actin-interacting proteins.