zheng-yi_chen@meei.harvard.edu
For investigator inquiries only
About My Research
Dr. Zheng-Yi Chen’s research interests include the understanding of the causes of hearing loss, the development of treatment by inner ear regeneration, gene editing, and gene therapy.
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 these 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.
Dr. Chen's laboratory has identified the retinoblastoma gene (Rb1) as the key gene controlling cell exit in hair cells and supporting cells, with implication in hair cell regeneration in young mammalian inner ears. Using chicken and zebrafish models, they identified key genes including c-Myc in hair cell regeneration in lower vertebrates. They demonstrated that the reprogramming by two factors c-Myc and Notch1 is 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 currently working on elucidating the mechanisms underlying proliferation and regeneration. They are also developing strategies to regenerate adult hair cells for hearing restoration in animal models. Their goal is to develop a treatment for hearing loss by inner ear regeneration in humans.
Dr. Chen’s laboratory also 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, no therapy is currently available. The next frontier in genetic hearing loss is the development of treatment.
The laboratory is applying the transformative CRISPR/Cas9-mediated genome editing technology to treat genetic hearing loss. They developed the delivery of RNP (ribonucleoprotein) into the mammalian inner ear in vivo. They demonstrated RNP delivery of CRISPR/Cas9 genome editing agents into mouse models of human genetic hearing loss with the rescue of hearing. They have produced a pig model for human genetic hearing loss to further advance the work into the clinic. Their work opened a new avenue in developing a treatment for genetic hearing loss by editing based therapy.
Age-related and noise-induced hearing loss (ARHL and NIHL) are considered different entities that require separate treatments. Dr. Chen’s laboratory uncovered that hair cell overexpression of ISL1, an inner ear progenitor gene, resulted in protection from both ARHL and NIHL in mice. Hair cells expressing ISL1 are resistant to damage or cell death (apoptosis). This study underscores a common mechanism underlying ARHL and NIHL.
The laboratory is additionally developing an AAV (adeno-associated virus) based gene therapy for 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 multiple approaches as treatment for different types of hearing loss in humans.
- Gene Expression by Mouse Inner Ear Hair Cells during Development. J Neurosci. 2015 Apr 22; 35(16):6366-80.
- XIRP2, an actin-binding protein essential for inner ear hair-cell stereocilia. Cell Rep. 2015 Mar 24; 10(11):1811-8.
- Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Proc Natl Acad Sci U S A. 2015 Jan 06; 112(1):166-71.
- Cationic lipid-mediated delivery of proteins enables efficient protein-based genome editing in vitro and in vivo. Nat Biotechnol. 2015 Jan; 33(1):73-80.
- Disrupting the interaction between retinoblastoma protein and Raf-1 leads to defects in progenitor cell proliferation and survival during early inner ear development. PLoS One. 2013; 8(12):e83726.
- Hair cell overexpression of Islet1 reduces age-related and noise-induced hearing loss. J Neurosci. 2013 Sep 18; 33(38):15086-94.
- Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein. Biochem Biophys Res Commun. 2013 Jan 11; 430(2):700-5.
- Analysis of miR-376 RNA cluster members in the mouse inner ear. Int J Exp Pathol. 2012 Dec; 93(6):450-7.
- Overlapping and distinct pRb pathways in the mammalian auditory and vestibular organs. Cell Cycle. 2011 Jan 15; 10(2):337-51.
- Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2. Am J Hum Genet. 2010 Jan; 86(1):65-71.
- Mitochondrial haplotype and phenotype of 13 Chinese families may suggest multi-original evolution of mitochondrial C1494T mutation. Mitochondrion. 2009; 9(6):418-28.
- Diverse expression patterns of LIM-homeodomain transcription factors (LIM-HDs) in mammalian inner ear development. Dev Dyn. 2008 Nov; 237(11):3305-12.
- Hair cell regeneration. Curr Opin Neurobiol. 2008 Aug; 18(4):377-82.
- Expression studies of osteoglycin/mimecan (OGN) in the cochlea and auditory phenotype of Ogn-deficient mice. Hear Res. 2008 Mar; 237(1-2):57-65.
- The a1 subunit of nicotinic acetylcholine receptors in the inner ear: transcriptional regulation by ATOH1 and co-expression with the ? subunit in hair cells. J Neurochem. 2007 Dec; 103(6):2651-64.
- The α1 subunit of nicotinic acetylcholine receptors in the inner ear: transcriptional regulation by ATOH1 and co-expression with the g subunit in hair cells. J Neurochem. 2007; (Epub ahead of print).
- Cell cycle, differentiation and regeneration: where to begin? Cell Cycle. 2006 Nov; 5(22):2609-12.
- Essential role of retinoblastoma protein in mammalian hair cell development and hearing. Proc Natl Acad Sci U S A. 2006 May 09; 103(19):7345-50.
- An isoform of GTPase regulator DOCK4 localizes to the stereocilia in the inner ear and binds to harmonin (USH1C). J Mol Biol. 2006 03 31; 357(3):755-64.
- Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein. Science. 2005 Feb 18; 307(5712):1114-8.
- Islet-1 expression in the developing chicken inner ear. J Comp Neurol. 2004 Sep 06; 477(1):1-10.
- Applications of genomics in the inner ear. Pharmacogenomics. 2003 Nov; 4(6):735-45.
- Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum Mol Genet. 2003 May 15; 12(10):1155-62.
- Understanding inner ear development with gene expression profiling. J Neurobiol. 2002 Nov 05; 53(2):276-85.
- A novel locus for autosomal dominant non-syndromic deafness (DFNA41) maps to chromosome 12q24-qter. J Med Genet. 2002 Aug; 39(8):567-70.
- An inner ear gene expression database. J Assoc Res Otolaryngol. 2002 Jun; 3(2):140-8.
- Vascular defects and sensorineural deafness in a mouse model of Norrie disease. J Neurosci. 2002 Jun 01; 22(11):4286-92.
- Mutations in GJA1 (connexin 43) are associated with non-syndromic autosomal recessive deafness. Hum Mol Genet. 2001 Dec 01; 10(25):2945-51.
- Myosin-VIIb, a novel unconventional myosin, is a constituent of microvilli in transporting epithelia. Genomics. 2001 Mar 15; 72(3):285-96.
- Functional expression of exogenous proteins in mammalian sensory hair cells infected with adenoviral vectors. J Neurophysiol. 1999 Apr; 81(4):1881-8.
- The genomic structure of the gene defective in Usher syndrome type Ib (MYO7A). Genomics. 1997 Feb 15; 40(1):73-9.
- Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients. Am J Hum Genet. 1996 Nov; 59(5):1074-83.
- Molecular cloning and domain structure of human myosin-VIIa, the gene product defective in Usher syndrome 1B. Genomics. 1996 Sep 15; 36(3):440-8.
- Mapping of unconventional myosins in mouse and human. Genomics. 1996 Sep 15; 36(3):431-9.
- Characterization and mapping of the mouse NDP (Norrie disease) locus (Ndp). Mamm Genome. 1996 Feb; 7(2):93-7.
- A bidirectional YAC walk from the Norrie disease (NDP) locus. Genomics. 1995 Feb 10; 25(3):644-9.
- Norrie disease and MAO genes: nearest neighbors. Hum Mol Genet. 1995; 4 Spec No:1729-37.
- Mutations in the Norrie disease gene. Hum Mutat. 1995; 5(4):285-92.
- Norrie disease. Molecular Genetics of Inherited Eye Disorders (Wright AF and Jay B, ed). 1994; 321-338.
- A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993 Oct; 5(2):180-3.
- Characterization of a mutation within the NDP gene in a family with a manifesting female carrier. Hum Mol Genet. 1993 Oct; 2(10):1727-9.
- Norrie disease gene: characterization of deletions and possible function. Genomics. 1993 May; 16(2):533-5.
- Carrier detection in X-linked immunodeficiencies. II: An X inactivation assay based on differential methylation of a line-1 repeat at the DXS255 locus. Immunodeficiency. 1993; 4(1-4):213-5.
- Carrier detection in X-linked immunodeficiencies. I: A PCR-based X chromosome inactivation assay at the MAOA locus. Immunodeficiency. 1993; 4(1-4):209-11.
- Molecular genetics and inheritance of human MAO-A and MAO-B. Monoamine Oxidase: Its Role in Normal and Disease States. 1993; 95-112.
- The hypervariable DXS255 locus contains a LINE-1 repetitive element with a CpG island that is extensively methylated only on the active X chromosome. Genomics. 1992 Nov; 14(3):598-603.
- An X chromosome inactivation assay based on differential methylation of a CpG island coupled to a VNTR polymorphism at the 5' end of the monoamine oxidase A gene. Hum Mol Genet. 1992 Nov; 1(8):662.
- Organization of the human monoamine oxidase genes and long-range physical mapping around them. Genomics. 1992 Sep; 14(1):75-82.
- Isolation and characterization of a candidate gene for Norrie disease. Nat Genet. 1992 Jun; 1(3):204-8.
- Characterization of a YAC containing part or all of the Norrie disease locus. Hum Mol Genet. 1992 Jun; 1(3):161-4.
- An X chromosome inactivation assay based on differential methylation of a CpG island coupled to a VNTR polymorphism at the 5' end of the monoamine oxidase A gene. Hum Mol Genet. 1992 Jun; 1(3):187-94.
- The Norrie disease gene maps to a 150 kb region on chromosome Xp11.3. Hum Mol Genet. 1992 May; 1(2):83-9.
- Molecular Study of Human Sex Chromosomes. 1992.
- Structure of the human gene for monoamine oxidase type A. Nucleic Acids Res. 1991 Aug 25; 19(16):4537-41.
- The properdin structural locus (Pfc) lies close to the locus for tissue inhibitor of metallothionine proteases (Timp) on the mouse X chromosome. Genomics. 1991 Aug; 10(4):1030-4.
- Dinucleotide repeat polymorphism at the MAOA locus. Nucleic Acids Res. 1991 Feb 11; 19(3):689.
- An approach to cloning the proximal locus for X-linked retinitis pigmentosa. Degenerative Retinopathies: Advances in Clinical and Genetic Research. 1991; 119-128.
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