Harvard Catalyst Profiles

My research interests include 1). Molecular basis of deafness. 2). Functional genomics of hearing. 3). Inner ear hair cell regeneration. 4). Gene therapy for genetic hearing loss.

My work involves understanding the molecular basis of genetic deafness. I mapped and cloned one of the first human deafness genes, Norrie disease. I identified an allelic disorder, XFEVR, which is caused by mutations in Norrie gene. I characterized the mouse model for Norrie disease and demonstrated that the defects in the inner ear vasculature are the primary cause of deafness, which is one of the first cases of genetic deafness due to vasculature defects. I cloned two myosin genes, myosin VIIa and Myosin VIIb, and defects in myosin VIIa is responsible for Usher type Ib syndrome, a deafness-blindness syndrome. Further, we have shown that a recessive non-syndromic deafness is caused by mutations in prestin, an outer hair cell motor protein.

I am the first to use the functional genomics approach to study mammalian inner ear. I used microarray analysis to comprehensively study the gene expression of the developing mouse vestibular organ, the utricle, through its life cycle, and identified the major pathways involved at single-cell-type resolution. I am the first to comprehensively profile genes expressed in human inner ear. We have obtained the most complete survey of genes expressed in the mammalian inner ear, as well as in purified sensory hair cells, with the highest cellular resolution. This study laid the foundation for our work on hair cell regeneration and inner ear stem cell biology.

Mammalian inner ear lacks the capacity to regenerate hair cells. Using functional genomics approach, we identified the retinoblastoma gene (Rb1) as a gene essential in cell cycle exit and postmitotic maintenance of hair cells. We showed that when the Rb1 is deleted in the inner ear, normally postmitotic hair cell progenitor cells undergo proliferation, which then proceed normally with hair cell specification, differentiation and become functional.

We created a hair-cell-specific Rb1 deletion model, and showed that the adult Rb1-null vestibular hair cells continue to proliferate and are functional at both the cellular and the system levels. In postnatal cochlea, Rb1-null hair cells die due to impaired maturation. Thus, pRb is also required for cochlear hair cell maturation and survival. The study is the first to demonstrate that in mammals functional hair cells can be regenerated through cell cycle re-entry of existing hair cells, which has important implication in regeneration of other postmitotic cells including neurons. Using the chick hair cell regeneration model for expression profiling, we identified two pathways: c-Myc and Fgf, in hair cell regeneration. Using the zebrafish model, we demonstrate that spontaneous regeneration of the lateral line neuromast hair cells can be suppressed by blocking c-myc or Fgf pathways pharmacologically or genetically. One of the most important goals is to renew proliferation and hair cell regeneration in adult and aged mammalian inner ear. We have recently identified a mechanism by which adult and aged mammalian inner ear cells can re-enter cell cycle. Further under a proper condition the dividing cells can transdifferentiate to functional hair cells that are connected to ganglion neurons. This exciting work sets a stage to restore hearing in deaf animals.

1 in 500 newborns suffer from genetic hearing loss and no treatment is yet available. Recent progress in CRSIPR/Cas9 mediated genome editing makes it possible to permanently edit DNA sequences as new treatment for genetic hearing loss. In collaboration with David Liu at Harvard University, we have developed a method by which the key CRISPR enzyme Cas9 can be directly delivered into mammalian inner ear in vivo for genome editing. Further using a genetic hearing loss transgenic mouse model we have demonstrated that such approach could lead to hearing restoration. We are expanding this technology so it can be applied to treat different types of genetic hearing loss. This study has implication in the development of CRISPR/Cas9 to treat other types of genetic diseases.