Enhancing hair cell regeneration in mouse and human inner ear

Enhancing hair cell regeneration in mouse and human inner ear

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06529
Award Value: 
$3,091,595
Disease Focus: 
Hearing Loss
Stem Cell Use: 
Adult Stem Cell
Status: 
Active
Public Abstract: 
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.
Statement of Benefit to California: 
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.
Progress Report: 

Year 1

Inner ear hair cells are required to detect motion both from sounds and linear acceleration. Loss of these cells cause hearing loss and balance disorders, therefore, our laboratory has been studying progenitor cells that have the potential to regenerate lost hair cells, either at baseline or after manipulation, with the eventual goal of restoring hearing and balance functions. In the last 6 months, we have continues our work on characterize one such hair cell progenitor cell population locating in the utricle, one of the 5 vestibular organs in the inner ear. Use transgenic mice, we have successfully pinpointed their identity and also follow their fate after damage to the hair cells both in culture and in the whole animal. We have also established normative measurement of vestibular function immediately after damage and during hair cell regeneration long after injury. Ongoing work involves pharmacologic and transgenic manipulation of these hair cell progenitors with the goal of coercing them to regenerate more. In parallel, we have established a culture system to study whether a similar progenitor cell population exists in human utricular tissues, and an important aspect of this work will be translating successful approaches in the mouse system immediately to human tissues.

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