Zheng-Yi Chen, D.Phil.

Harvard Medical School

Associate Professor of Otolaryngology

Massachusetts Eye and Ear

Associate Scientist

Research Summary

Research Area Affiliations

Research Summary

Dr. Chen’s research interests include functional genomics of hearing, inner ear hair cell regeneration, mechanisms and treatment for age-related and noise-induced hearing loss (ARHL and NIHL) and gene therapy for hereditary deafness.

One of the most common causes of hearing loss is the loss of hair cells, the inner ear sensory cells that detect sound and sense balance. Regeneration of hair cells in the adult mammalian inner ear has been the most prominent obstacle to overcome. Dr. Chen’s laboratory takes a functional genomics approach to systematically study gene expression patterns during mouse inner ear development. They have identified the retinoblastoma gene (Rb1) as the key gene controlling cell exit in hair cells and supporting cells, with an implication in hair cell regeneration in young mammalian inner ears. Using chicken and zebrafish models, they identified new key genes in hair cell regeneration in lower vertebrates. They demonstrated that the function of the genes are sufficient to induce proliferation of hair cells and supporting cells in adult and aged mammalian inner ears, resulting in regeneration of functional hair cells. His laboratory is working on elucidating the mechanisms underlying proliferation and regeneration, and they are developing strategies to regenerate adult hair cells for hearing recovery in animal models and to regenerate human hair cells.

Dr. Chen’s laboratory has a long-standing interest in genetic hearing loss. The laboratory has been involved in cloning and characterizing numerous deafness genes. Though more than one hundred genetic deafness genes have been identified, still no therapy is currently available. The next frontier in genetic hearing loss is the development of treatment. The laboratory has recently shown that proteins can be directly delivered into the mammalian inner ear in vivo with functional consequences. Dr. Chen's laboratory has used protein delivery to demonstrate genome editing in the inner ear hair cells by CRISPR/Cas9 technology. They are now working on combining protein delivery and genome editing as a potential new treatment for genetic hearing loss. This combinatory approach should open the doors to the efficient study of virtually all genes in the inner ear.

Using a transgenic approach, Dr. Chen’s laboratory uncovered that hair cell overexpression of Isl1, an inner ear progenitor gene, resulted in protection from age-related and noise-induced hearing loss (ARHL & NIHL) in mice. Hair cells expressing Isl1 are resistant to cell death (apoptosis). This study underscores a common mechanism underlying ARHL and NIHL. Using mass sequencing, the laboratory is investigating the Isl1 targets and screening for compounds that can be used for protection against ARHL and NIHL.

Dr. Chen’s long-term research goals are to identify genes and functional pathways that govern the development, function and disease state of the inner ear, and to develop therapies for different types of deafness in humans.

Select Publications

Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Liu XZ, Ouyang XM, Xia XJ, Zheng J, Pandya A, Li F, Du LL, Welch KO, Petit C, Smith RJ, Webb BT, Yan D, Arnos KS, Corey D, Dallos P, Nance WE, Chen ZY. Hum Mol Genet. 2003;12(10):1155-62.

Vascular defects and sensorineural deafness in a mouse model of Norrie disease. Rehm HL, Zhang DS, Brown MC, Burgess B, Halpin C, Berger W, Morton CC, Corey DP, Chen ZY. J Neurosci. 2002;22(11):4286-92.

Proliferation of Functional Hair Cells in Vivo in the Absence of the Retinoblastoma Protein. Sage C, Huang M, Karimi K, Gutierrez G, Vollrath MA, Zhang DS, Garcia_Anoveros J, Hinds PW, Corwin JT, Corey DP, Chen ZY. Science. 2005;307(5712):1114-1118.

Essential role of retinoblastoma protein in mammalian hair cell development and hearing. Sage C, Huang M, Vollrath MA, Brown CM, Hinds PW, Corey DP, Vetter DE and Chen ZY. Proc Natl Acad Sci U S A. 2006;103:7345-7350.

Hair cell overexpression of Islet1 reduces age-related and noise-induced hearing loss.
Huang M, kantardzhieva A, Scheffer D, Liberman MC and Chen ZY. J Neurosci. 2013; 18(38):15086-94.

Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Zuris JA, Thompson DB, Shu Y, Guilinger JP, Bessen JL, Hu JH, Maeder ML, Joung JK, Chen ZY and Liu DR. Nat Biotechnol. 2014 Oct 30. doi: 10.1038/nbt.3081. [Epub ahead of print]

Notch inhibition induces mitotically-generated hair cells in mammalian cochleae via activating the Wnt pathway. Li W, Wu J, Yang J, Sun S, Chai R, Chen ZY and Li H. Proc Natl Acad Sci U S A 2014, 2015 Jan 6;112(1):166-71.

View a complete list of publications on pubmed.gov »

Biosketch

Education

B.Sc. Genetics, Sichuan University, 1984
D.Phil. Human Genetics, Oxford University, 1992

Postgraduate Training

01/92-12/94: Research Fellowship: Neurology, Massachusetts General Hospital

Professional Memberships

1991 - present: The American Society of Human Genetics, member
1995 - present: The Association for Research in Otolaryngology, member
2005 - present: Society for Neuroscience, member
2012 - present: American Society of Gene and Cell Therapy, member

Awards and Honors

2004: Pfizer/AFAR Innovations in Aging Research Program, American Federation for Aging Research
2005: Research Leader, The 2005 Scientific American 50, Scientific American