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Section on Sensory Cell Biology
Lisa L. Cunningham, Ph.D., Chief
Diagram of cross-section of the utricle showing hair cells and supporting cells.
Supporting cells (labeled red with anti-Sox2) infected with adenovirus driving GFP expression.
Mouse utricles with hair cells labeled with antibodies against calmodulin (green) and calbindin (red). Left panel is a control utricle showing type I (red) and type II (green) hair cells. Right panel is a utricle treated with cisplatin, which is toxic to hair cells. At this low cisplatin concentration, type I hair cells are killed while type II hair cells survive.
Our research is focused on the mechanosensory hair cells that are the receptor cells of hearing and balance. Specifically, we are interested in the molecular signals that regulate the survival, homeostasis, and death of these cells. Mammalian hair cells are terminally differentiated and are not regenerated when they are lost. Therefore, human hair cells must survive and function for up to a century (or longer) in order to transduce sound and head movement into the neural signals of hearing and balance throughout a normal lifespan. During this lengthy period of time, the hair cell may encounter multiple potentially toxic stimuli, including exposure to excessive sound and/or exposure to therapeutic drugs with ototoxic side effects. Hair cells must be able to respond rapidly and effectively to these and other potentially cytotoxic stimuli if they are to survive and continue to function.
We are examining the signals that mediate the survival and death of hair cells under stress. We are currently studying the role of stress-induced proteins called heat shock proteins (HSPs) in protecting against hair cell death. Our studies use an in vitro preparation of the adult mouse utricle (a balance organ in the inner ear), which is the best-characterized model system for in vitro studies of mature mammalian hair cells. Using this preparation, we have shown that HSPs inhibit hair cell death caused by both major classes of ototoxic drugs, namely the aminoglycoside antibiotics and the antineoplastic agent cisplatin. In addition, we have shown that mice that constitutively express HSP70 are resistant to hearing loss and cochlear hair cell death caused by systemic aminoglycoside exposure. Our studies indicate that HSP induction is a critical stress response in the inner ear that can promote survival of hair cells exposed to major stressors.
Currently our studies are broadly divided into two groups: 1) those aimed at understanding the molecular mechanisms underlying the protective effects of HSPs and 2) those aimed at translating our findings into clinical therapies to prevent hearing loss caused by exposure to ototoxic drugs.
Click above to see a video demonstration of the mouse utricle dissection and infection of supporting cells using adenovirus.
DC Cherry Blossom Festival 2015. L-R: Shimon Francis, Elyssa Monzack, Lisa Cunningham, Lindsey May, Aaron Rusheen
Back row, L-R: Shimon Francis, Andrew Breglio. Middle row, L-R: Aaron Rusheen, Lisa Cunningham, Matthew Ryals. Front row, L-R: Katharine Fernandez, Lindsey May
- Lisa L. Cunningham, Ph.D. Senior Investigator +1 301 443 2766 (Send e-mail (link sends e-mail))
- Andrew Breglio Clinical Fellow +1 301 827 4172 (Send e-mail (link sends e-mail))
- Katharine Fernandez, Au.D., Ph.D. Research Scientist +1 301 496 5699 (Send e-mail (link sends e-mail))
- Shimon Francis, Ph.D. Postdoctoral IRTA Fellow +1 301 443 2766 (Send e-mail (link sends e-mail))
- Lindsey May Biologist +1 301 443 5884 (Send e-mail (link sends e-mail))
- Baker, TG; Roy, S; Brandon, CS; Kramarenko, IK; Francis, SP; Taleb, M; Marshall, KM; Schwendener, R; Lee, F-S; Cunningham, LL (2015): Heat shock protein-mediated protection against cisplatin-induced hair cell death. J. Assoc Res Otolaryngol 16:67-80.
- Chien, WW; Monzack, EL; McDougald, D; Cunningham, LL (2015): Gene therapy for sensorineural hearing loss. Ear and Hearing 36(1):1.
- Cunningham, LL and Tucci, DL (2015): Restoring synaptic connections in the inner ear after noise damage. New England Journal of Medicine 372(2):181. Invited review.
- Wang, T; Chai, R; Kim, GS; Pham, N; Jansson, L; Nguyen, D-H; Kuo, B; May, LA; Zuo, J; Cunningham, LL; Cheng, AG (2015): Damage-recruited Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in neonatal mouse utricle. Nature Communications.
- Chien, WW; McDougald, D; Roy, S; Fitzgerald, TS; Cunningham, LL (2015): Cochlear gene transfer mediated by adeno-associated virus: comparison of two surgical approaches. Laryngoscope.
- Monzack, EL; May, LA; Roy, S; Gale, JE; Cunningham, LL (2015): Live imaging the phagocytic activity of inner ear supporting cells in response to hair cell death. Cell Death and Differentiation doi: 10.1038/cdd.2015.48.
- Drummond, MC; Barzik, M; Bird, JE; Zhang, D-S; Lechene, CP; Corey, DP; Cunningham, LL; Friedman, TB (2015): Live-cell imaging of actin dynamics reveals mechanisms of stereocilia development and homeostasis in the inner ear. Nature Communications 6:6873.
- Monzack, EL and Cunningham, LL (2013): Lead roles for supporting actors: Critical roles for inner ear supporting cells. Hearing Research 303:20-9.
- Roy, S; Ryals, MM; Botty, A; Fitzgerald, TS; Cunningham, LL (2013): Sound preconditioning therapy in mice inhibits ototoxic hearing loss. J. Clinical Investigation 123(11):4945–4949.
- May, LM; Kramarenko, II; Brandon, CS; Voelkel-Johnson, C; Roy, S; Truong, K; Francis, SP; Monzack, EL; Lee, F-S; Cunningham, LL (2013): Inner ear supporting cells protect hair cells by secreting HSP70. J. Clinical Investigation 123(8):3577–3587.
- Brandon, CS; Voelkel-Johnson, C; May, LA; Cunningham, LL (2012): Dissection of adult mouse utricle and adenovirus-mediated supporting cell infection. Journal of Visualized Experiments. 61, doi:10.3791/3734. Published online 28 March 2012.
- Francis SP; Kramarenko II; Brandon CS; Lee FS; Baker TG; Cunningham LL (2011). Celastrol inhibits aminoglycoside-induced ototoxicity via heat shock protein 32. Cell Death & Disease 2, e195; doi:10.1038/cddis.2011.76. Published online 25 August 2011.
- Taleb, M; Brandon, CS; Lee, F-S; Harris, KC; Dillmann, WH; Cunningham, LL(2009): Hsp70 inhibits aminoglycoside-induced hearing loss and cochlear hair cell death Cell Stress Chaperones 14:427-437.