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
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 maintenance of hair cells.
Research focus I: Discovery of novel proteins involved in hearing and deafness
The process of hair cell mechanotransduction converts mechanical energy, caused by sound or head acceleration, into electrical signals that can be interpreted by the brain. This process takes place in the sensory hair cell, in a specialized organelle called hair bundle. Roughly a third of all gene mutations causing hearing loss encode proteins that reside in the sensory hair bundle (Raviv et al., 2010 and hereditaryhearingloss.org). Identification and characterization of hair bundle proteins is thus expected to facilitate the discovery of novel deafness genes. Our lab uses Proteomics methods to identify novel proteins that are located in the hair bundle, and we follow up the initial discovery by an in depth characterization of protein function, using cell biology, molecular biology, protein biochemistry and mouse genetics. Using this multifaceted approach, we have already identified several genes that are involved in hearing loss (e.g. FSCN2), and we are currently working on several novel proteins with possible roles in hearing and deafness.
Research focus II: Neurodegeneration and protection of sensory hair cells
The mechanosensitive hair cells in the inner ear do not regenerate, meaning they cannot be replaced once irreparably damaged and lost. It is therefore crucial to identify measures to protect and repair damaged hair cells. Sensory hair cells are sensitive to many different stress factors, both environmental and endogenous to the cell. Hair cell damage can occur due to age, genetic predispositions, noise and drugs such as certain antibiotics and anti-cancer drugs. A major goal of our lab is to understand the molecular mechanisms and pathways that underlie hair cell damage and death, with special emphasis on drug-induced hair cell damage. Using a combination of cell biology, molecular biology, proteomics and transgenic mouse models, we are probing cellular signaling networks for their involvement in the healthy and pathological state of the sensory hair cell, with the goal of identifying novel pathways and therapeutic targets to prevent hearing loss.
Current Research projects
1.) 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 and 3) generate transgenic mouse models to evaluate the role of these putative deafness genes in vivo.
Techniques used: Mass spectrometry, cell biology, protein biochemistry, generation of transgenic mouse models
Model organism: Mouse, chicken
2.) How do ototoxic drugs kills hair cells, and how can we prevent it?
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.
Techniques used: Organ explant cultures, in vivo hair cell damage models, cell biology, transgenic mouse models, proteomics.
Model organism: Mouse, chicken
3.)Monitoring protein dynamics in hair cells using microscopy
In this project, we will study the immediate changes that are correlated with oxidative and mechanical stressto hair cells. Our goal is to visualize the dynamic processes that follow the disruption of the mechanotransduction complex. Of equal interest are the dynamic processes that enable the regeneration of the mechanotransduction complex, possibly involving the redistribution of mechanotransduction proteins. In order to observe the dynamics of bundle proteins (especially transduction complex components) in response to oxidative and mechanical stress, we will express tagged proteins in hair cells and monitor the movement of these proteins using in vivofluorescence microscopy.
Visualization of cellular and molecular events is a powerful tool, and the introduction of the Green fluorescent protein (GFP) and its variants has enabled us to visualize the action of proteins in their native cellular environment.
Introducing and expressing genes of interest into hair cells has been difficult so far. Our approach is to generate transgenic Xenopus frogs that express a GFP-tag ged version of our proteins, and to monitor these proteins in isolated frog hair cells.
Techniques used: Xenopus transgenesis, confocal fluorescence microscopy, DNA cloning techniques
Model organisms: Xenopus tropicalis, rat, mouse
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.
M’hamed Grati, Jung-Bum Shin, Michael D. Weston, James Green, Manzoor A. Bhat, Peter G. Gillespie, and Bechara Kachar (2012) Localization of PDZD7 to the Stereocilia Ankle-Link Associates this Scaffolding Protein with the Usher Syndrome Protein Network. J Neurosci. 2012 Oct 10;32(41):14288-93.
Kateri J. Spinelli, John E. Klimek, Phil A. Wilmarth, Jung-Bum Shin, Song-Seok 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. The R109H variant of fascin-2, a developmentally regulated actin crosslinker in hair-cell stereocilia, underlies early-onset hearing loss of DBA/2J mice. J. Neurosci, 2010, 30(29): 9683-9694.
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. J Neurosci. 2006; 26(40):10188-98.
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.
Jung-Bum Shin, Carlos Martinez-Salgado, Paul A. Heppenstall and Gary R. Lewin. A T-type calcium channel required for normal function of a mammalian mechanoreceptor. Nat Neurosci. 2003 Jul; 6(7):724-30.