Funding opportunities

Enhancing hair cell regeneration in mouse and human inner ear

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06529
Principle Investigator: 
Institution: 
Funds requested: 
$3 091 595
Funding Recommendations: 
Recommended
Grant approved: 
Yes
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.
Review Summary: 
Executive Summary Specialized hair cells of the inner ear are required for both hearing and balance. While hair cells in the mammalian utricle (part of the balancing or vestibular system) show some limited capacity for regeneration, those of the cochlea (part of the hearing system) do not, and thus loss of such cells due to damage or disease leads to permanent hearing loss. The goal of this proposal is to explore the biology of candidate progenitor cells in the utricle and to determine whether these cells can be manipulated with growth factors to promote hair cell regeneration in the inner ear. Three aims have been proposed to achieve these objectives. In the first, the applicant will use in vitro experiments to characterize candidate progenitors and explore whether manipulation of a key signaling pathway can enhance hair cell regeneration in damaged human utricles. In the second, the applicant will use similar approaches in a transgenic model to elucidate the molecular mechanisms by which this regeneration occurs. Finally, the applicant will use an in vivo model of hair cell damage to explore the extent to which manipulation of this signaling pathway can restore function to the inner ear. Research Plan - Hearing loss due to destruction of inner ear hair cells affects a very large number of individuals, particularly those who are elderly or aging. Given that there are no current therapies to treat or reverse the underlying damage, the proposed research could have major impact. - The proposal is based on strong preliminary data and a solid experimental design. Reviewers particularly appreciated the elegant lineage tracing experiments and excellent use of imaging and electrophysiological assessments for characterizing hair cells. - The scientific rationale for focusing on endogenous stem cell sources over exogenous, or even autologous non-ear derived sources (for example, induced pluripotent stem cells) was not clearly articulated. - The translational potential of this proposal may be limited to vestibular disorders if cochlear hairs cell do not respond and regenerate by mechanisms similar to those of utricular progenitors. - The use of only a single cell marker to identify relevant progenitor cells in human utricles appeared problematic. - Some reviewers considered the supplies budget to be excessive. Principal Investigator (PI) - The PI is a surgeon-scientist and an established leader in hair cell regeneration. In addition to relevant clinical experience in treating patients with hearing loss, she/he has an excellent track record of funding and independent publications. - The proposed mentors are world-renowned experts in highly relevant fields of signal transduction, stem cell and hair cell biology. Each has a strong mentoring track record and will provide complementary expertise to the PI. - While reviewers found the mentoring plan to be effective and reasonable, they considered its lack of focus on translational activities (in favor of basic research) to be a weakness with respect to this funding initiative. Institutional Commitment - The applicant institution provides an outstanding, intellectually stimulating environment for physician-scientist career development, offering core services, adequate start up and lab space as well as protected time for research. - The applicant institution has an excellent track record in development of physician scientists, and a strong commitment to researchers and clinicians in the area of hearing loss. Responsiveness - While some reviewers considered the proposal to be responsive, others expressed concern that the disproportionate emphasis on basic research and use of animal model systems might effectively limit its nearer term potential for translation.
Conflicts: 

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