PROJECT SUMMARY (ABSTRACT)
Sensorineural hearing loss and vestibular dysfunction are most common sensory disorders affecting
millions worldwide 1–3. Auditory and vestibular functions require mechanosensitive hair cells, with hair cell loss
leading to permanent hearing loss and disabling vestibular dysfunction/hypofunction. Recently, the neonatal
mouse utricle, one of five vestibular organs that relies on hair cells to detect linear acceleration, was shown to
harbor robust numbers of progenitor cells 6,7. However, while the existence of both mitotic and non-mitotic
mechanisms in mammals is now clear, we currently lack understanding of the timing, location, and mechanisms
of cell fate decisions. In other systems, like the skin, it is known that fate decisions are made downstream of
stem cells and their transit amplifying populations, but we do not yet know the fates of these putative populations
in the inner ear 39. A central regulator of tissue homeostasis and stem cell maintenance across many organs is
the Wnt pathway 8, and this signaling cascade is upregulated in the inner ear 12. I hypothesize that following injury,
mitotic regeneration leads to different cell lineages in the neonatal utricular sensory epithelium, and that Wnt
activation directs more supporting cells to adopt the mitotic cell lineage. Gaining an in-depth understanding of
the sequence of events that drive mitotic regeneration post injury will reveal potential approaches to regenerate
hair cells and supporting cells, with the ultimate goal of restoring hearing and balance functions.
As a surgeon-scientist with a passion for treating patients with hearing and balance disorders, I am well
equipped to tackle the scientific questions outlined. My interests in the basic sciences stem from my
undergraduate years working on the genetics and development of the somatosensory cortex and studying the
olfactory system. During medical school, I saw the lack of therapies of patients with permanent hearing loss as
an opportunity, working on hair cell regeneration under the tutelage of renowned scientists, including Dr. Stefan
Heller and Dr. Roel Nusse (Jan et al., 2013, Development). As a resident in otolaryngology, I focused on gaining
the clinical and surgical expertise to treat patients and had the opportunity to continue basic science research
with a focus on hearing loss under Dr. Konstantina Stankovic. In order to gain advanced surgical skills and learn
state of the art techniques to study inner ear regeneration, I completed the T32 funded Clinician Scientist Training
Program in Otology & Neurotology. This program further allowed me to collect preliminary data and chart my
goals for this proposal as a new faculty member at UCSF. While I have extensive training in inner ear biology,
my knowledge is lacking in advanced mouse genetics, new single cell RNAseq technologies, and advanced
bioinformatics. Under the guidance of renowned stem cell physician-scientist Dr. Ophir Klein as my mentor at
UCSF, and expert inner ear surgeon-scientist, Dr. Alan Cheng as my co-mentor at Stanford, I am confident this
award will prepare me for scientific independence through the R01 grant mechanism.