THE ROLE OF E2F2 MODULATION OF RB1 IN COCHLEAR HAIR CELLS AND SUPPORTING CELLS

E2F2 对耳蜗毛细胞和支持细胞中 RB1 的调节作用

• 批准号: 8168360
• 负责人: Sonia M Rocha-Sanchez
• 金额: $ 28.55万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168360
• 关键词: Ablation; Adult; Age; Apoptosis; Biochemical; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cells; Computer Retrieval of Information on Scientific Projects Database; Cyclins; Disease; Ear; Effectiveness; Epithelium; Exhibits; Funding; Gene Proteins; Genetic; Grant; Hair Cells; Institution; Labyrinth; Molecular; Natural regeneration; Organ of Corti; Pathway interactions; Proliferating; Proteins; Research; Research Personnel; Resources; Retinoblastoma Protein; Role; Sensory; Source; Supporting Cell; System; Therapeutic; Tissues; United States National Institutes of Health; Variant; Vertebrates; base; deafness; hair cell regeneration; insight; member; mutant; non-genetic; transdifferentiation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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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