Professor of Research
Department of Regenerative Medicine and Stem Cell Biology
Keck School of Medicine of the University of Southern California
- embryonic development of the inner ear
- sensory hair cell regeneration
- cell cycle control during development
- cellular homeostasis ? DNA repair
- stem/progenitor cell biology
Research Overview1) Embryonic development of the inner ear:
Coordinating cell proliferation, growth and differentiation is crucial for the development of animal form. This project investigates the biochemical machinery responsible for this coordination. We are investigating the role and regulation of cyclin-dependent kinase inhibitors (CKIs) in the formation of the prosensory domains in the inner ear, the cells that give rise to the organ of Corti and the vestibular sensory areas. In addition, we are studying the biochemical basis for hair cell and supporting cell differentiation within the developing mosaic of the sensory epithelia, and its relation to the stability of the differentiated state. In particular, we are studying the epigenetic regulation of transcription associated with Notch-dependent signaling within this system.
2) Sensory cell regeneration - cellular reprogramming - postnatal changes in progenitors/stem cells of the inner ear: (Grad student project available in neurophysiological characterization following cellular reprogramming, as part of new Regenerative Medicine Initiative).
We are engaged in identifying and manipulating sensory progenitors/stem cells as potential targets for therapeutic approaches to hearing loss through regeneration. We have developed tools, in the form of cell-type specific markers and purification techniques, as well as cell culture methods for studying the behavior of sensory cell progenitors. We are currently using these tools to characterize the lineage and regenerative potential of specific cell populations within the postnatal inner ear.
A new project involves direct reprogramming of differentiated cells to the sensory lineage.
3) Homeostasis and repair in the aging nervous system: the cell cycle, DNA damage and DNA repair:
The goal of this project is to understand the basis for the lifelong homeostatic maintenance of permanently postmitotic cells in the nervous system, including the inner ear. Sensory hair cells, like most neurons, stop dividing either in the embryo or shortly after birth. If lost due to environmental stress (loud noise, chemotherapy agents, antibiotics, aging) these cells do not regenerate. This means that lifelong cell renewal/repair must occur on an ongoing basis in the absence of cell replacement and in the presence of strong control over cell division. These factors are associated with a heightened sensitivity to physiological/environmental stress. Our focus is on how the cell cycle machinery in hair cells contributes to their sensitivity to stress, and how these pathways interact with other homeostatic pathways, such as those involved in DNA damage and repair. Currently, we are studying mouse models of the human DNA repair disorder, Cockayne Syndrome, which is associated with aspects of premature aging, and, as our current research indicates, sensory-neural hearing loss.