Grant Award Details
To enhance the regeneration of sensory hair cells in human and mouse inner ear tissues to restore inner ear function. In this project, hair cell progenitors from human utricles will be characterized for the ability to regenerate ex vivo in the presence of Wnt agonists. In addition, utricles from transgenic mice will be cultured and putative progenitors fate mapped after damage and Wnt treatment. Finally, in vivo mouse models of utricle inner ear hair cell degeneration and regeneration will be characterized.
Grant Application Details
- Enhancing hair cell regeneration in mouse and human inner ear
Hearing loss (HL) is a permanent sensory disorder affecting over 278 million people worldwide. In the US and California, 20% of individuals suffer from this sensory deficit. Those affected range from newborns (2 per 1000), to children aged 3-17 (5 per 1000), to adults including the elderly (~33% in aged 65-74 and ~50% >85 years old). Existing treatments aim at improving the symptoms of HL, yet fail to reverse the main underlying pathology, loss of inner ear sensory hair cells (HC).
HCs are required for hearing and vestibular function. In the mammalian cochlea, no spontaneous HC regeneration occurs, whereas the vestibular organs exhibit a limited capacity to regenerate HCs. We propose to characterize candidate HC progenitors in vestibular tissues from transgenic mice and surgical patients. The most exciting aspect of this proposal is to understand the natural behavior of HC progenitors in mouse and human inner ear tissues, and whether growth factors enhance regeneration. We will also test whether regenerated HC are functional, and correlate the degree of HC regeneration with functional recovery at the whole animal level, where we can manipulate HC progenitors using transgenic or pharmacologic approaches. Upon completion, we will have learnt whether we can enhance HC regeneration by controlling HC progenitors. Moreover, our model systems may serve as a platform for other basic and preclinical studies aiming at regenerating HC to reverse HL.
Hearing loss (HL) is a permanent sensory disorder affecting over 278 million people worldwide. In the US and California, it is estimated that 20% (48 and 7.7 million, respectively) of individuals suffer from this sensory deficit. Those affected range from newborns (2 per 1000), to children aged 3-17 (5 per 1000), to adults including the elderly (~33% in aged 65-74 and ~50% >85 years old). Because normal hearing is essential for language development and communication, the impact of HL is profound. Currently, treatment options including hearing aids and cochlear implantation aim at improving the symptoms of HL, yet fail to reverse the main underlying pathology, loss of inner ear sensory hair cells (HC).
HCs are required for hearing and balance function. Recently, we have defined a population of HC progenitors in the mouse inner ear. Here, we will further characterize these progenitors in human and mouse utricles, the gravity sensing organ, and test if activating developmental signals augments regeneration. If one can direct somatic progenitor cells to replace lost HCs with new functional ones, one can envision therapeutics targeting somatic progenitors in patients with HL. Importantly, our model system will not only provide insights into whether signaling pathways can modulate HC regeneration, but also be used as a platform for pre-clinical drug testing. Successful therapeutics, if safe, can potentially benefit millions of Californians suffering from HL.
- Cell Rep (2019) Atoh1 Directs Regeneration and Functional Recovery of the Mature Mouse Vestibular System. (PubMed: 31291569)
- J Clin Invest (2018) Sox2 haploinsufficiency primes regeneration and Wnt responsiveness in the mouse cochlea. (PubMed: 29553487)
- Development (2015) Sensory hair cell development and regeneration: similarities and differences. (PubMed: 25922522)
- Nat Commun (2015) Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. (PubMed: 25849379)
- Development (2014) Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. (PubMed: 24496619)