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Principal Investigator: Taha A Jan
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $188,296
Funding agency: National Institute on Deafness and Other Communication Disorders
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.
Terms: <Ablation><Acceleration><Adopted><Affect><Auditory><Autoregulation><Award><Basal Transcription Factor><Basal transcription factor genes><Basic Research><Basic Science><Behavior><Beta Cadherin-Associated Protein><Beta-1 Catenin><Bio-Informatics><Bioinformatics><Biological><Biology><Body System><Body Tissues><CUL-2><Cell Body><Cell Communication and Signaling><Cell Growth and Maintenance><Cell Growth in Number><Cell Lineage><Cell Maintenance><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell division><Cells><Cellular Proliferation><Clinical><Corti Cell><Data><Decision Making><Development><Disabling><Dysfunction><Epithelium><Equilibrium><Event><Expression Signature><Faculty><Functional disorder><Funding><Gene Expression Profile><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Markers><Goals><Grant><HG38><Hair Cells><Hearing><Hearing Disorders><Hearing Loss><Hearing problem><Heterogeneity><Homeostasis><Human><Hypoacuses><Hypoacusis><In Vitro><Individual><Injury><Internal Ear><Intracellular Communication and Signaling><Knowledge><LGR5><LGR5 gene><Labyrinth><Lead><Learning><Location><M Phase><Maintenance><Mammalia><Mammals><Mentors><Mice><Mice Mammals><Mitosis><Mitosis Stage><Mitotic><Modeling><Modern Man><Molecular><Murine><Mus><Natural regeneration><Neonatal><Olfactory Pathways><Olfactory system><Operative Procedures><Operative Surgical Procedures><Organ><Organ System><Otolaryngology><Otology><PRO2286><Pathway interactions><Patients><Pb element><Persons><Physicians><Physiological Homeostasis><Physiopathology><Population><Progenitor Cells><Proliferating><Regeneration><Regenerative Medicine><Research><Scientist><Sensorineural Deafness><Sensorineural Hearing Loss><Sensory><Sensory Disorders><Sensory Hearing Loss><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Somatosensory Cortex><Supporting Cell><Surgeon><Surgical><Surgical Interventions><Surgical Procedure><System><Techniques><Technology><Therapeutic><Tissues><Training><Training Programs><Transcription Factor Proto-Oncogene><Transcription factor genes><Transmission><Utricle structure><Utricles><Vestibular><Vestibular System Function><Vestibular System Impairment><Vestibular defect><Vestibular dysfunction><Vestibular function><Vestibular problems><Work><auditory disease><auditory disorder><auditory dysfunction><auditory problem><balance><balance disorder><balance function><balance impairment><beta catenin><biologic><biological signal transduction><biomarker identification><cell behavior><cellular behavior><developmental><disturbed balance><dysfunctional hearing><ear hair cell><equilibration disorder><equilibrium disorder><experiment><experimental research><experimental study><experiments><gene biomarker><gene expression biomarker><gene expression pattern><gene expression signature><gene marker><gene signature biomarker><genetic biomarker><hair cell regeneration><hearing challenged><hearing defect><hearing deficient><hearing deficit><hearing difficulty><hearing disease><hearing dysfunction><hearing impairment><hearing restoration><heavy metal Pb><heavy metal lead><identification of biomarkers><identification of new biomarkers><in silico><in vivo><in vivo Model><injured><injuries><inner ear><insight><interest><marker identification><medical college><medical schools><member><mouse genetics><mouse model><murine model><neonatal injury><neonatal mice><olfactory circuitry><olfactory circuits><otorhinolaryngology><overexpress><overexpression><pathophysiology><pathway><permanent hearing loss><progenitor><progenitor cell regeneration><progenitor cell self renewal><progenitor regeneration><progenitor self renewal><programs><regenerate><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><regeneration based therapy><regeneration following injury><regeneration therapy><regenerative><regenerative therapeutics><regenerative therapy><restore hearing><scRNA-seq><school of medicine><self-renew><self-renewal><sensorineural hearing impairment><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skills><small molecule><somesthetic sensory cortex><spatiotemporal><stem><stem and progenitor cell regeneration><stem and progenitor cell self renewal><stem cell regeneration><stem cell self renewal><stem cells><surgery><tissue regeneration><tissue regrowth><tissue renewal><tissue specific regeneration><transcription factor><transcriptional profile><transcriptional signature><transmission process><undergrad><undergraduate><undergraduate student><vestibular deficit><vestibular impairment><vestibular system><vestibular system dysfunction><β-catenin>