This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In nearly all cells in the body, dynamic variation in the ratios of all three hyper-phosphorylated pocket proteins (pRBs) is directly correlated with cell proliferation, cellular quiescence, and apoptosis. Compared to other tissues, the biochemical and molecular pathways of the pRBs in the inner ear are relatively unexplored. Likewise, the effects of quantitative manipulation of this cell cycle's central node in the neurosensory cells of the ear and its potential to promote hair cell (HC) and supporting cell (SC) proliferation is yet to be determined. Unlike lower vertebrates, adult mammalian HCs do not regenerate. Loss of mammalian HCs cells, caused by genetic and non-genetic factors, is becoming an increasing problem as people age, resulting in deafness and vestibular disorders. Unveiling useful mechanisms of cell cycle regulation may offer the possibility to generate new cells out of SCs and/or remaining HCs, thus providing the cellular basis to induce HC regeneration in the mammalian ear. Recent studies have provided proof of principle for two sets of therapies: the use of the cyclin system or pocket protein gene (Rb1) to promote proliferation, and the effectiveness of Atoh1 to induce transdifferentiation (TD) of SC into HC. Combined, these two approaches can mimic the ability of lower vertebrates to regenerate HC. However, beyond the proof of principle, current attempts to regulate cell cycle through genetic ablation of Rb1 are not likely to safely repopulate lost HC and SC. Preliminary assessment of the three pRB members, Rb1, Rbl1 (p107) and Rbl2 (p130) revealed that all of them are expressed in the inner ear and exhibit extensive differences and similarities with one another along and across the organ of Corti. Deletion of any pRB leads to additional rows of HC and SC. Using various conditional and complete null mutants, we will determine the ability of SCs to proliferate as a result of quantitative manipulation of the inherent ratio of the pRBs in the inner ear sensory epithelia in the presence and absence of pre-existent HCs. These approaches are prone to provide insights on the therapeutic applicability of pRB manipulation in SC proliferation and HC regeneration.
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