Sensorineural Hearing and Hearing Loss

We aim to understand molecular mechanisms of neurodegenerative hearing loss so that we can develop better treatments. Biological therapies to halt or reverse progressive sensorineural hearing loss (SNHL) are lacking. To identify promising, targetable pathways to treat SNHL, we conducted a metabolomic and network analysis of pharmacotherapies for SNHL (Muurling and Stankovic, 2014). We validated key findings from that study using large epidemiologic data sets, in collaboration with Dr. Curhan of Harvard School of Public Health (e.g. Curhan, Stankovic et al, 2015). Focusing on secreted molecules, we provided the first description of the proteome of human perilymph using mass spectrometry techniques (Lysaght et al, 2011). We discovered that osteoprotegerin, a secreted cytokine (from the TNFa superfamily) that typically inhibits bone remodeling, is highly expressed by cochlear neurons and promotes their survival (Kao et al, 2013). This suggests a new approach for SNHL treatment, based on drug repurposing. We identified GATA3 as a novel regulator of osteoprotegerin (Kao and Stankovic, 2015). We discovered that another member of the TNFa superfamily, “TNFa-Related Apoptosis-Inducing Ligand” (TRAIL), promotes sensorineural degeneration in the inner ear via death-receptor signaling (Kao et al, 2016), suggesting a strategy to prevent such degeneration. We demonstrated that a synthetically made AAV vector, called Anc80L65, enables safe and efficient gene transfer to the mammalian inner ear, paving the way for novel gene therapy for deafness (Landegger et al, 2017).

Publications

Sagers JE, Landegger LD, Worthington S, Nadol JB, Stankovic KM. Human Cochlear Histopathology Reflects Clinical Signatures of Primary Neural Degeneration. Scientific Reports 7, 4884 (2017).

Landegger LD*, Pan B*, Askew C*, Wassmer S, Gluck S, Galvin A, Forge A, Taylor R, Stankovic KM&, Holt JR&, Vandenberghe LH&A Synthetic AAV Vector Enables Safe and Efficient Gene Transfer to the Mammalian Inner Ear. Nature Biotechnology. 2017 Feb 6. (*/& = equal contribution)

Landegger LD, Dilwali S, Stankovic KM. Neonatal Murine Cochlear Explant Technique as an in vitro Screening Tool in Hearing Research. Journal of Visualized Experiments (JoVE)124, e55704, doi:10.3791/55704 (2017).

Lin BM, Li WQ, Curhan SG, Stankovic KM, Qureshi A, Curhan GC. Skin Pigmentation and Risk of Hearing Loss in Women. American Journal of Epidemiology. 2017 May 19:1-10.

Lin BM, Curhan SG, Wang M, Eavey R, Stankovic KM, Curhan GC. Prospective Study of Gastroesophageal Reflux, Use of Proton Pump Inhibitors and H2-Receptor Antagonists, and Risk of Hearing Loss. Ear and Hearing. 2017 Jan/Feb; 38(1): 21-27.

Lin BM, Curhan SG, Wang M, Eavey R, Stankovic KM, Curhan GC. Duration of Analgesic Use and Risk of Hearing Loss in Women. American Journal of Epidemiology 2017 Jan 1; 185(1): 40-47.

Groth JB, Kao SY, Briët MC, Stankovic KM. Hepatocyte Nuclear Factor-4 Alpha in Noise-Induced Cochlear NeuropathyDevelopmental Neurobiology. 2016; Apr 25.

Kao SY, Soares VY, Kristiansen AG, Stankovic KM. Activation of TRAIL-DR5 Pathway Promotes Sensorineural Degeneration in the Inner Ear. Aging Cell. 2016;15(2):301-8.

West JS, Low JC, Stankovic KM. Revealing Hearing Loss: A Survey of How People Verbally Disclose Their Hearing Loss. Ear and Hear. 2016; 37(2):194-205.

Lin BM, Curhan SG, Wang M, Eavey R, Stankovic KM, Curhan GC. Hypertension, Diuretic Use, and Risk of Hearing Loss. American Journal of Medicine. 2016; 129(4):416-22.

Curhan SG, Stankovic KM, Eavey RD, Wang M, Stampfer MJ, Curhan GC. Carotenoids, vitamin A, vitamin C, vitamin E, and folate and risk of self-reported hearing loss in women. American Journal of Clinical Nutrition. 2015; 102(5):1167-75.

Kao SY, Stankovic KM. Transactivation of human osteoprotegerin promoter by GATA-3. Scientific Reports. 2015; 5:12479.

Jensen JB, Lysaght AC, Liberman MC, Qvortrup K, Stankovic KM. Immediate and Delayed Cochlear Neuropathy After Noise Exposure in Pubescent Mice. PLoS One. 2015; 10(5):e0125160.

Balasubramanian  R, Choi J, Francescatto L, Willer JR, Horton ER, Asimacopoulos EP, Stankovic KM, Plummer L, BuckCL, Quinton R, Nebesio TD, Mericq V,  MerinoPM, Meyer BF, MoniesD, Gusella JF, Tassan NA, Katsanis N, Crowley WF Jr. Functionally Compromised CHD7 Alleles in Patients with Isolated GnRH Deficiency. Proceedings of the National Academy of Sciences 2014; 111(50):17953-8.

Lysaght A, Yuan Q, Fan Y, Kalwani N, Caruso P, Cunnane M, Lanske B, Stankovic KM.  FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice. Plos One 2014; 9(9):e107681.

Muurling T, Stankovic KM. Metabolomic and Network Analysis of Pharmacotherapies for Sensorineural Hearing Loss. Otology and Neurotology 2014; 35(1):1-6.

Platt M, Dilwali S, Elackatuu A, Parikh J, Stankovic KM. Mining Immune Epitopes in the Inner Ear. Otolaryngology Head and Neck Surgery 2014;150(3):460-463.

Kao SY*, Kempfle JS*, Jensen JB*, Perez-Fernandez D, Lysaght A, Edge AS, Stankovic KM. Loss of Osteoprotegerin Expression in the Inner Ear Causes Degeneration of the Cochlear Nerve and Sensorineural Hearing Loss. Neurobiology of Disease April 2013; 56C: 25-33 (* = equal contribution). Featured on the cover page of August issue.

Stamatiou GA, Stankovic KM. A Comprehensive Network and Pathway Analysis of Human Deafness Genes. Otology and Neurotology 2013; 34(5):961-70.

Lysaght A, Kao SY, Paulo J, Merchant S, Steen H, Stankovic KM. Proteome of Human Perilymph. Journal of Proteome Research. 2011; 10(9): 3845-51.

Stankovic KM, Hennessy AM, Herrmann B, Mankarious LA. Cochlear Implantation in Children with DFN3 Congenital X-Linked Deafness due to Novel Mutations in POU3F4 Gene.  Annals Otology Rhinolology and Laryngology 2010; 119(12): 815-822.

Sugawara M, Murtie JC, Stankovic KM, Liberman MC, Corfas G. Dynamic Patterns of NT3 Expression in the Postnatal Mouse Inner Ear.  Journal of Comparative Neurology. 2007; 501(1): 30-37.

Stankovic KM, Rio C, Xia A, Sugawara M, Adams JC, Liberman MC, Corfas G. Survival of Adult Spiral Ganglion Neurons Requires erbB Receptor Signaling in the Inner Ear.  Journal of Neuroscience 2004; 24(40): 8651-61.

Stankovic KM, Corfas G. Real-time Quantitative RT-PCR for Low-Abundance Transcripts in the Inner Ear: Analysis of Neurotrophic Factor Expression. Hearing Research 2003; 185(1-2): 97-108. 

Stankovic KM. A Method for Evaluation of Multiparameter Nonlinear Models Illustrated on a Computational Model of Auditory-Nerve Rate-Level Curves. In Greenberg S, Slaney M (Eds). Computational Models of Auditory Function; IOS Press, Amsterdam, 2001;17-28.

Stankovic KM, Guinan JJ Jr. Medial Efferent Effects on Auditory-Nerve Responses to Tail-Frequency Tones II: Alteration of Phase. J Acoustical Society of America. 2000; 108: 664-678. 

Stankovic KM, Guinan JJ Jr. Medial Efferent Effects on Auditory-Nerve Responses to Tail-Frequency Tones I: Rate Reduction. J Acoustical Society of America. 1999; 106: 857-869.

Stankovic KM, Brown D, Alper SL, Adams JC. Localization of pH Regulating Proteins H+ATPase and Cl-/HCO3- Exchanger in the Guinea Pig Inner Ear. Hearing Research 1997; 114: 21-34.

Guinan JJ Jr, Stankovic KM. Medial Efferent Inhibition Produces Largest Equivalent Attenuation at Moderate to High Sound Levels in Cat Auditory-Nerve Fibers. J Acoustical Society of America 1996; 100: 1680-1690.

Stankovic KM, Adams JC, Brown D. Immunolocalization of Aquaporin CHIP in the Guinea Pig Inner Ear. American Journal of Physiology (Cell) 1996; 269: C1450-1456.