- BS, University of Tubingen
- PhD, Free University of Berlin
- Postdoc, Oregon Health Sciences University
- Assistant Professor, Neuroscience
Hearing loss is America’s leading disability, affecting millions of people of all ages. To develop preventative and restorative clinical approaches, it is crucial to understand how the hearing process works on the cellular and molecular level. Hearing is mediated by sensory hair cells, part of a highly specialized neuroepithelium in the inner ear. The goal of our lab is to unravel the mechanisms that mediate the development, function, and degeneration of hair cells.
Research focus I: Discovery of novel proteins involved in hearing and deafness
Our lab uses a combination of proteomics, protein biochemistry, cell biology and mouse genetics tools to discover novel components involved in the molecular process of hearing. In short, we 1) sequence proteins in the sensory hair cell using mass spectrometry, 2) compare the proteomics data with genetic data to identify possible deafness genes, 3) characterize the function of these proteins, and 4) use the CRISPR/Cas9 system to generate transgenic mouse models to evaluate the role of these putative deafness genes in vivo. Presently, we are applying this workflow on 10 different potential deafness genes.
Research focus II: Neurodegeneration and protection of sensory hair cells
Aminoglycosides comprise a highly potent class of antibiotics, but their clinical use is limited due to nephrotoxicity and ototoxicity. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside ototoxicity remains limited, and methods for clinical intervention have yet to emerge. We have recently found that the regulation of protein homeostasis in hair cells is severely affected by aminoglycosides. Protein homeostasis is at the center of general cellular homeostasis, and its dysregulation can activate various stress pathways leading to cellular degeneration and death. We are currently exploring the involvement of novel stress pathways in aminoglycoside-induced hair cell degeneration, with special emphasis on the discovery of novel drugs to prevent hair cell degeneration by blocking stress pathways.
Research focus III: CRISPR/Cas-mediated gene therapy of deafness mutations
Gene therapy to repair deafness mutations is a highly relevant goal in deafness research. In a remarkably short time period, the CRISPR/Cas9 system has emerged as arguably the most efficient genome engineering tool to date. The goal of this project is to engineer a novel, modified CRISPR system that allows packaging in an adeno-associated vector, which presently is the only system for in vivo delivery of genetic material into adult sensory hair cells. This tool will be used to repair deafness mutations in a mouse model.
- Francis S, Krey J, Krystofiak E, Cui R, Nanda S, Xu W, Kachar B, Barr-Gillespie P, Shin J. A short splice form of Xin-actin binding repeat containing 2 (XIRP2) lacking the Xin repeats is required for maintenance of stereocilia morphology and hearing function. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2015;35(5): 1999-2014. PMID: 25653358 | PMCID: PMC4315831
- Mann Z, Thiede B, Chang W, Shin J, May-Simera H, Lovett M, Corwin J, Kelley M. A gradient of Bmp7 specifies the tonotopic axis in the developing inner ear. Nature communications. 2014;5 3839. PMID: 24845721 | PMCID: PMC4264580
- Avenarius M, Saylor K, Lundeberg M, Wilmarth P, Shin J, Spinelli K, Pagana J, Andrade L, Kachar B, Choi D, David L, Barr-Gillespie P. Correlation of actin crosslinker and capper expression levels with stereocilia growth phases. Molecular & cellular proteomics : MCP. 2013;13(2): 606-20. PMID: 24319057 | PMCID: PMC3916657
- Francis S, Katz J, Fanning K, Harris K, Nicholas B, Lacy M, Pagana J, Agris P, Shin J. A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013;33(7): 3079-93. PMID: 23407963
- Krey J, Wilmarth P, Shin J, Klimek J, Sherman N, Jeffery E, Choi D, David L, Barr-Gillespie P. Accurate label-free protein quantitation with high- and low-resolution mass spectrometers. Journal of proteome research. 2013;13(2): 1034-44. PMID: 24295401 | PMCID: PMC3946283
- Shin J, Krey J, Hassan A, Metlagel Z, Tauscher A, Pagana J, Sherman N, Jeffery E, Spinelli K, Zhao H, Wilmarth P, Choi D, David L, Auer M, Barr-Gillespie P. Molecular architecture of the chick vestibular hair bundle. Nature neuroscience. 2013;16(3): 365-74. PMID: 23334578 | PMCID: PMC3581746
- Grati M, Shin J, Weston M, Green J, Bhat M, Gillespie P, Kachar B. Localization of PDZD7 to the stereocilia ankle-link associates this scaffolding protein with the Usher syndrome protein network. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2012;32(41): 14288-93. PMID: 23055499 | PMCID: PMC3518401
- Spinelli K, Klimek J, Wilmarth P, Shin J, Choi D, David L, Gillespie P. Distinct energy metabolism of auditory and vestibular sensory epithelia revealed by quantitative mass spectrometry using MS2 intensity. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(5): E268-77. PMID: 22307652 | PMCID: PMC3277109
- Zhao H, Williams D, Shin J, Brügger B, Gillespie P. Large membrane domains in hair bundles specify spatially constricted radixin activation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2012;32(13): 4600-9. PMID: 22457506 | PMCID: PMC3324267
- Shin J, Longo-Guess C, Gagnon L, Saylor K, Dumont R, Spinelli K, Pagana J, Wilmarth P, David L, Gillespie P, Johnson K. The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair-cell stereocilia, underlies early-onset hearing loss of DBA/2J mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010;30(29): 9683-94. PMID: 20660251 | PMCID: PMC2922854
- Shin J, Streijger F, Beynon A, Peters T, Gadzala L, McMillen D, Bystrom C, Van der Zee C, Wallimann T, Gillespie P. Hair bundles are specialized for ATP delivery via creatine kinase. Neuron. 2007;53(3): 371-86. PMID: 17270734 | PMCID: PMC1839076
- Gagnon L, Longo-Guess C, Berryman M, Shin J, Saylor K, Yu H, Gillespie P, Johnson K. The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006;26(40): 10188-98. PMID: 17021174
- Senften M, Schwander M, Kazmierczak P, Lillo C, Shin J, Hasson T, Géléoc G, Gillespie P, Williams D, Holt J, Müller U. Physical and functional interaction between protocadherin 15 and myosin VIIa in mechanosensory hair cells. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2006;26(7): 2060-71. PMID: 16481439 | PMCID: PMC2712835
- Shin J, Adams D, Paukert M, Siba M, Sidi S, Levin M, Gillespie P, Gründer S. Xenopus TRPN1 (NOMPC) localizes to microtubule-based cilia in epithelial cells, including inner-ear hair cells. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(35): 12572-7. PMID: 16116094 | PMCID: PMC1194908