THE OVERALL GOAL of our research program is to protect and regenerate the inner ear in order to improve patients’ hearing health. We strive to understand the mechanisms of development, regeneration, and protection of mammalian sensory hair cells using state-of-the-art technologies and collaborative approaches.
 

Development

Hair cells are born and then precisely organized into rows, a highly-ordered structure critical for our hearing organ to function properly. Understanding how this complex organ develops provides us with invaluable insights into how inner ear malformation relates to congenital hearing loss and also expedites our efforts in regenerating this organ. Numerous signaling pathways including Wnt signaling have been implicated to regulate these critical developmental steps.

Our group is interested in determining how Wnt signaling dictates these diverse processes and interact with other key signaling pathways. In particular, we aim to probe individual components of the pathway to determine their roles in governing sensory cell fate and planar cell polarity.

Regeneration

Regenerating the mammalian cochlea is a monumental task yet it remains our ultimate goal. Our two-pronged approach is based on our findings that the newborn mouse cochlea and utricle both regenerate lost hair cells by defined progenitors.

By interrogating the genetic landscape of cochlear and utricular hair cell progenitors, we hope to better understand mechanisms governing early phases of regeneration. Using in vitro and in vivo models of hair cell regeneration in the utricle, we aim to characterize the mechanisms and physiology of vestibular regeneration at both the cellular and organ levels.

Aminoglycoside Ototoxicity

Aminoglycosides are potent antibiotics that cause irreversible hearing loss, making aminoglycoside ototoxicity one of the most preventable causes of hearing loss. We aim to design and build a new version of antibiotic that is non-ototoxic. In a collaborative effort with Tony Ricci’s lab, we have recently generated the first generation of non-ototoxic aminoglycoside derivatives. We now focus on understanding the structural-activity relationships of these compounds by studying their interactions with bacterial ribosomes, trafficking into bacteria and hair cells, antimicrobial activities and ototoxicity. With these information, we plan to optimize the next generation of drug design and synthesis.

PUBLICATIONS

2015

Protein-engineered hydrogel encapsulation for 3D culture of murine cochlea. Chang DT, Chai R, Dimarco R, Heilshorn SC, Cheng AG. Otol Neurotol 36(3):531-8 doi: 10.1097/MAO.0000000000000518.

Designer aminoglycosides prevent cochlear hair cell loss and hearing loss. Huth M, Han KH, Soutadeh K, Hsieh YJ, Effertz T, Vu AA, Verhoeven S, Hsieh MH, Greenhouse RJ, Cheng AG, Ricci AJ. J Clin Invest pii: 77424. doi: 10.1172/JCI77424.

Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Wang T, Chai R, Kim GS, Pham N, Jansson L, Nguyen DQ, Kuo B, May LA, Zuo J, Cunningham LL, Cheng AG. Nat Commun 6:6613. doi: 10.1038/ncomms7613.

Intraoperative acupuncture for posttonsillectomy pain: A randomized, double-blind, placebo-controlled trial. Tsao GJ, Messner AH, Seybold J, Sayyid ZN, Cheng AG, Golianu B. Laryngoscope doi: 10.1002/lary.25252.

Making sense of Wnt signaling—linking hair cell regeneration to development. Jansson L, Kim GS, Cheng AG.  Front Cell Neurosci 9:66. doi: 10.3389/fncel.2015.00066.

Sensory cell development and regeneration: similarities and differences. Atkinson PJ, Huarcaya Najarro E, Sayyid ZN, Cheng AG. Development 142(9), 1561-1571 doi:10.1242/dev.114926.

2014

Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. Cox BC, Chai R, Lenoir A, Liu Z, Zhang LL, Nguyen DH, Chalasani K, Steigelman KA, Fang J, Cheng AG, Zuo J. Development 141: 816-829 doi:10.1242/dev.103036.

2013

Transient, afferent input-dependent, postnatal niche for neural progenitor cells in the cochlear nucleus. Volkenstein S, Oshima K, Sinkkonen ST, Corrales CE, Most SP, Chai R, Jan TA, Cheng AG, Heller S. Proc Natl Acad Sci U S A. 2013; Aug 27; 110(35):14456-61.

A simple method for purification of vestibular hair cells and non-sensory cells, and application for proteomic analysis.Herget M, Scheibinger M, Guo Z, Jan TA, Adams CM, Cheng AG, Heller S. PLoS One. 2013 Jun 4;8(6):e66026.

Integrity and regeneration of mechanotransduction machinery regulate aminoglycoside entry and sensory cell death. Vu AA, Nadaraja GS, Huth ME, Luk L, Kim J, Chai R, Ricci AJ, Cheng AG. PLoS One. 2013; 8 (1): e54794

Tympanic border cells are Wnt-responsive and can act as progenitors for postnatal mouse cochlear cells. Jan TA, Chai R, Sayyid ZN, van Amerongen R, Xia A, Wang T, Sinkkonen ST, Zeng YA, Levin JR, Heller S, Nusse R, Cheng AG. Development. 2013; 140 (6): 1196-206

2012

Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea. Chai R, Kuo B, Wang T, Liaw EJ, Xia A, Jan TA, Liu Z, Taketo MM, Oghalai JS, Nusse R, Zuo J, Cheng AG. Proc Natl Acad Sci U S A. 2012; 109 (21): 8167-72

2011

Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. Chai R, Xia A, Wang T, Jan TA, Hayashi T, Bermingham-McDonogh O, Cheng AG. J Assoc Res Otolaryngol. 2011; 12 (4): 455-69

Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. Alharazneh A, Luk L, Huth M, Monfared A, Steyger PS, Cheng AG, Ricci AJ. PLoS One. 2011; 6 (7): e22347

Intrinsic regenerative potential of murine cochlear supporting cells. Sinkkonen ST, Chai R, Jan, T, Hartman B, Laske R, Gahlen F, Sinkkonen W, Cheng AG, Oshima K, Heller. Scientific Reports. 2011; 1 (26): DOI:10.1038/srep0002

Isolating LacZ-expressing cells from mouse inner ear tissues using flow cytometry. Jan TA, Chai R, Sayyid ZN, Cheng AG. J Vis Exp. 2011; (58): e3432

Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Huth ME, Ricci AJ, Cheng AG. Int J Otolaryngol. 2011: 2011 937861