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Section on Sensory Cell Biology
Lisa L. Cunningham, Ph.D., Chief
Research Statement
Diagram of cross-section of the utricle showing hair cells and supporting cells.
Localization of cisplatin in the human inner ear using laser ablation inductively-coupled plasma mass spectrometry (ICP-MS). Red and yellow colors indicate higher signal intensity.
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.
Research in the Section on Sensory Cell Biology is focused on the mechanosensory hair cells that are the receptor cells of hearing and balance. Hair cells transduce sound energy or head movement into neural input to the brain. Hair cells are sensitive to death from a variety of stresses, including noise trauma, aging, genetic mutations, and exposure to therapeutic drugs with ototoxic side effects. The Section on Sensory Cell Biology conducts basic, translational, and clinical studies on hair cell degeneration and hearing loss in the mature inner ear and develops therapeutic strategies to safeguard hearing.
- Our basic science studies examine the mechanisms that underlie sensory hair cell death and survival.
- Our translational studies use this mechanistic knowledge to guide the rational design of therapies aimed at preventing or reversing hearing loss in humans.
- Our clinical studies test the efficacy of potential protective therapies in humans receiving ototoxic drugs.
Our basic science studies focus on the signal transduction and intercellular communication pathways that are activated in response to hair cell stress and death. We showed that induction of heat shock proteins (HSPs) can protect hair cells against major stresses, including exposure to both classes of ototoxic drugs (i.e., the aminoglycoside antibiotics and cisplatin). Pro-survival induction of HSP expression is relatively low in hair cells and is more robust in surrounding cell types, including the glia-like supporting cells and resident macrophages. These data indicate that hair cells may have a reduced capacity to induce autonomous pro-survival signaling in response to stress, and that non-cell-autonomous signals from supporting cells and macrophages function as critical mediators of pro-survival signaling when hair cells are under stress. Our current basic science studies are designed to examine the intercellular signaling that occurs when hair cells are under stress.
Our translational studies consist of preclinical experiments aimed at developing therapies to preserve hearing in humans exposed to ototoxic drugs. Cisplatin is a widely used drug that is used to treat solid tumors. Cisplatin treatment results in permanent hearing loss for a significant proportion of patients treated with the drug. We have developed a mouse model of cisplatin ototoxicity, and we have used this model to examine the mechanisms underlying cisplatin-induced hearing loss. Our data indicate that cisplatin readily enters the inner ear, but unlike most other organs, the inner ear has very little capacity for eliminating cisplatin. Thus cisplatin remains in the inner ear indefinitely after treatment. Currently, our translational work is aimed at developing therapies to prevent cisplatin uptake into the inner ear.
Our clinical studies are aimed at testing the efficacy of protective therapies in humans taking ototoxic drugs. We are examining the capacity for the cholesterol-lowering drugs known as statins to protect against cisplatin-induced hearing loss in humans. We are conducting a prospective study in patients with head and neck cancer who are undergoing cisplatin-based chemoradiation. The goal of this project is to test the hypothesis that statin use reduces hearing loss in these patients.
Click above to see a video demonstration of the mouse utricle dissection and infection of supporting cells using adenovirus.
Cunningham lab group enjoying the DC Wharf, spring 2018.
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
Lab Personnel
- 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))
Selected Publications
A complete list of publications is available at NCBI's MyBibliography.
- Cunningham, LL and Tucci, DL (2017): Hearing loss in adults. New England Journal of Medicine. Dec 21;377(25):2465-2473. doi: 10.1056/NEJMra1616601. PMID: 29262274.
- Breglio, AM; Rusheen, AE; Shide, ED; Fernandez, KA; Spielbauer, KK; McLachlin, KM; Hall, MD; Amable, L; Cunningham, LL (2017): Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nature Communications. Nov 21;8(1):1654. doi: 10.1038/s41467-017-01837-1.
- Francis, SP and Cunningham, LL (2017): Non-autonomous cellular responses to ototoxic drug-induced stress and death. Frontiers in Cellular Neuroscience. 23 Aug 2017. doi: 10.3389/fncel.2017.00252.
- Isgrig, K; Shteamer, JR; Belyantseva, IA; Drummond, MC; Fitzgerald, TS; Jones, SM; Griffith, AJ; Friedman, TB; Cunningham, LL; Chien, WW (2017): Gene therapy restores balance and auditory functions in a mouse model of Usher syndrome. Molecular Therapy 25(3):780. doi: 10.1016/j.ymthe.2017.01.007
- Zhu, B; Saleh, J; Isgrig, K; Cunningham, LL; Chien, WW (2017): Hearing loss after round window surgery in mice is due to middle ear effusion. Audiology & Neurotology 21:356. doi: 10.1159/000449239.
- Chien, WW; Isgrig, K; Roy, S; Belyantseva, I; Drummond, MC; May, LA; Fitzgerald, TS; Friedman, TB; Cunningham, LL (2016): Gene therapy restores hair cell stereocilia morphology in inner ears of deaf whirler mice. Molecular Therapy February 24:1. doi: 10.1038/mt.2015.150.
- 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.