Jung-Bum Shin, Ph.D.
Department of Neuroscience
Ph.D., 2003, Free University Berlin, Germany
2003-2009 Postdoctoral Fellow, Oregon Health Science University,
Oregon Hearing Research Center and Vollum Institute
Webpage: Shin Lab
Hair Cell Damage and Repair
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. Given that mammalian hair cells do not regenerate, the repair of hair cell damage is important for continued auditory function throughout life. Our lab therefore focuses on the molecules and mechanisms involved in hair cell repair and maintenance.
Our research interests can be divided into three categories:
- Repair and maintenance of hair cell function and structure
Sensory hair cells of the inner ear are exposed to continuous mechanical stress, causing damage over time. The maintenance of hair cells is further challenged by damage from a variety of other ototoxic factors, including loud noise, aging, genetic defects, and ototoxic drugs. This damage can manifest in many forms, from dysfunction of the hair cell mechanotransduction complex to hair cell death. Because mammalian hair cells do not regenerate, the repair of hair cell damage is important for continued auditory function throughout life. The majority of my research program is devoted to the question of how the hair cell repairs itself.
I) Repair of the stereocilia actin core: We hypothesize that a protein called XIRP2 is essential for the repair of the actin cytoskeletal structures that make up the mechanosensory hair bundle.
II) Cuticular plate: A more recent interest concerns molecules (e.g. LMO7) that are indispensable for the integrity of the cuticular plate, which provides the mechanical foundation for the hair bundle.
III) Repair of the hair cell mechanotransduction complex: A long-standing interest of the lab has been the repair of the tip link and mechanotransduction (MET) complex. Our most recent work has established that Myosin-VIIa is the tip link motor that provides tension to the MET complex and is essential for the sensitivity of hearing. Our next step is to study the mechanisms that mediate the repair of the tip link and MET complex, which can be damaged by external stresses such as age and noise.
2. How do ototoxic drugs kill hair cells, and how can we prevent it?
Aminoglycosides and cisplatin comprise a potent class of antibiotics and anticancer drugs, respectively, but their clinical use is limited due to ototoxicity. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside and cisplatin ototoxicity is insufficient, 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 and cisplatin. Protein homeostasis is at the center of general cellular homeostasis, and its dysregulation can activate various stress pathways leading to cellular degeneration and death. In addition, we are exploring the involvement of novel stress and cell death pathways (such as necroptosis) in aminoglycoside- and cisplatin-induced hair cell death, with special emphasis on the discovery of novel drugs to prevent hair cell degeneration by blocking stress pathways.
3. Discovery of novel proteins involved in hearing and deafness
This is our discovery pipeline, by which we identify, in an unbiased manner, proteins that are involved in hair cell function. We identify novel hair bundle proteins using a proteomics approach, characterize the function of these proteins, and generate mouse models to evaluate their role in hearing in vivo. Presently, we are applying this workflow on 10+ different potential deafness genes.
- Sihan Li, Andrew Mecca, Jeewoo Kim, Giusy A. Caprara, Elizabeth L. Wagner, Ting-Ting Du, Leonid Petrov, Wenhao Xu, Runjia Cui, Ivan T. Rebustini, Bechara Kachar, Anthony W. Peng, Jung-Bum Shin (2020). Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex. Nature Communications. 11; 2066
- Elizabeth L. Wagner and Jung-Bum Shin. Mechanisms of Hair Cell Damage and Repair (2019). Trends in Neurosciences. 2019 Apr 13.
- Ting-Ting Du, Dewey JB, Wagner EL, Cui R, Heo J, Park JJ, Francis SP, Perez-Reyes E, Guillot SJ, Sherman NE, Xu W, Oghalai JS, Kachar B, Jung-Bum Shin. LMO7 deficiency reveals the significance of the cuticular plate for hearing function (2019). Nature Communications. 10(1):1117.
- Doug Ruhl, Du TT, Wagner EL, Choi JH, Li S, Reed R, Kim K, Freeman M, Hashisaki G, Lukens JR, Shin JB. Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity (2019). Journal of Neuroscience. 39(15):2951-2964.
- Brian Nicholas BD, Francis S, Wagner EL, Zhang S, Jung-Bum Shin. Protein Synthesis Inhibition and Activation of the c-Jun N-Terminal Kinase Are Potential Contributors to Cisplatin Ototoxicity (2017). Front Cell Neurosci. 11:303
- Shimon Francis, Jocelyn F. Krey, Evan S Krystofiak, Cui R, Sonali Nanda, Wenhao Xu, Bechara Kachar, Peter G. Barr-Gillespie, Jung-Bum Shin. (2015) 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. Journal of Neuroscience 35(5):1999-2014.
- Zoe F. Mann, Benjamin R. Thiede, Weise Chang, Jung-Bum Shin, Helen M. May-Simera, Michael Lovett, Jeffrey T. Corwin, Matthew W. Kelley. A gradient of Bmp7 specifies the tonotopic axis in the developing inner ear (2014). Nature Communications. 2014 20;5:3839
- Matthew R. Avenarius, Katherine W. Saylor, Megan R. Lundeberg, Phillip A. Wilmarth, Jung-Bum Shin, Kateri J. Spinelli, James M. Pagana, Leonardo Andrade, Bechara Kachar, Dong-Seok Choi, Larry L. David, Peter G. Barr-Gillespie. Correlation of actin crosslinker and capper expression levels with stereocilia growth phases (2014). Mol Cell Proteomics. 13(2):606-20.
- Jocelyn F. Krey, Phillip A. Wilmarth, Jung-Bum Shin, John Klimek, Nicholas E. Sherman, Erin D. Jeffery, Dong-Seok Choi, Larry L. David, Peter G. Barr-Gillespie. Accurate label-free protein quantitation with high- and low-resolution mass spectrometers (2014). J Proteome Res. ;13(2):1034-44.
- Shimon P. Francis, Josh Katz, Kathryn D. Fanning, Kimberly A. Harris, Brian D. Nicholas, Michael M. Lacy, James Pagana, Paul F. Agris and Jung-Bum Shin (2013) A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity, Journal of Neuroscience. 13;33(7):3079-93
- Jung-Bum Shin, Jocelyn F. Krey, Ahmed Hassan, Zoltan Metlagel, Andrew N Tauscher, James M Pagana, Nicholas E. Sherman, Erin D. Jeffery, Kateri J. Spinelli, Hongyu Zhao, Phillip Wilmarth, Dongseok Choi, Larry L. David, Manfred Auer and Peter G. Barr-Gillespie (2013) Molecular architecture of the chick vestibular hair bundle. Nature Neuroscience. 16(3):365-74
- Hongyu Zhao, Diane E. Williams, Jung-Bum Shin, Britta Brügger, Peter G. Gillespie (2012) Large membrane domains in hair bundles specify spatially constricted radixin activation. Journal of Neuroscience. 32(13):4600-9.
- Kateri J. Spinelli, John E. Klimek, Phil A..Wilmarth, Jung-Bum Shin, Dong-Seuk Choi, Larry L. David, Peter G. Gillespie (2012). Distinct energy metabolism of auditory and vestibular sensory epithelia revealed by quantitative mass spectrometry using MS2 intensity. Proc Natl Acad Sci U S A. 109(5): E268-77.
- Jung-Bum Shin, Chantal M. Longo-Guess, Leona H. Gagnon, Katherine W. Saylor, Rachel A. Dumont, Kateri J. Spinelli, James M. Pagana, Phillip A. Wilmarth, Larry L. David, Peter G. Gillespie, and Kenneth R. Johnson(2010). The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair-cell stereocilia, underlies early-onset hearing loss of DBA/2J mice. Journal of Neuroscience 30 (29): 9683-9694
- Jung-Bum Shin, James Pagana, Peter G. Gillespie. Twist-off purification of hair bundles. Methods Mol Biol.2009; 493: 241-56.
- Jung-Bum Shin, Femke Streijger, Andy Beynon, Theo Peters, Laura Gadzala, Debra McMillen, Cory Bystrom, Catharina E. Van der Zee, Theo Wallimann, Peter G. Gillespie. Hair bundles are specialized for ATP delivery via creatine kinase. Neuron. 2007; 53(3):371-86
- Leona H. Gagnon, Chantal M. Longo-Guess, Mark Berryman, Jung-Bum Shin, Katherine W. Saylor, Heping Yu, Peter G. Gillespie, and Kenneth R. Johnson. The chloride intracellular channel protein CLIC5 is expressed at high levels in hair cell stereocilia and is essential for normal inner ear function. Journal of Neuroscience. 2006;26(40):10188-98.
- Mathias Senften, Martin Schwander, Piotr Kazmierczak, Concepcion Lillo, Jung-Bum Shin, Tama Hasson, Gwenaëlle S. G. Géléoc, Peter G. Gillespie, David Williams, Jeffrey R. Holt, and Ulrich Müller. Physical and functional interaction between protocadherin 15 and myosin VIIa in mechanosensory hair cells. Journal of Neuroscience. 2006; 26(7):2060-71.
- Jung-Bum Shin, Dany Adams, Martin Paukert, Maria Siba, Samuel Sidi, Michael Levin, Peter G. Gillespie, and Stefan Gründer. Xenopus TRPN1 (NOMPC) localizes to microtubule-based cilia in epithelial cells, including inner ear hair cells. Proc Natl Acad Sci U S A. 2005; 102 (35):12572-7.
*both authors contributed equally to the work