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: 8360395
• 负责人: Sonia M Rocha-Sanchez
• 金额: $ 28.83万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360395
• 关键词: Ablation; Adult; Age; Apoptosis; Biochemical; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cells; Cyclins; Disease; Ear; Effectiveness; Epithelium; Exhibits; Funding; Gene Proteins; Genetic; Grant; Hair Cells; Labyrinth; Molecular; Molecular Biology; National Center for Research Resources; Natural regeneration; Organ of Corti; Pathway interactions; Principal Investigator; Proliferating; Proteins; RB1 gene; Research; Research Infrastructure; Resources; Retinoblastoma Protein; Role; Sensory; Source; Supporting Cell; System; Therapeutic; Tissues; United States National Institutes of Health; Variant; Vertebrates; base; cost; deafness; hair cell regeneration; insight; member; mutant; neurosurgery; non-genetic; transdifferentiation

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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在体内几乎所有的细胞中，所有三个超磷酸化口袋的比率的动态变化， 蛋白质（pRB）与细胞增殖、细胞静止和凋亡直接相关。相比 与其他组织相比，内耳中pRBs的生化和分子途径相对较少， 未开发的同样，定量操作该细胞周期的中心节点在细胞周期中的作用也是非常重要的。 耳神经感觉细胞及其促进毛细胞（HC）和支持细胞（SC）的潜力 扩散情况尚待确定。与低等脊椎动物不同，成年哺乳动物的毛细胞不会再生。 由于遗传和非遗传因素引起的哺乳动物HCs细胞的丢失正在成为一个日益严重的问题。 随着人们年龄的增长，这一问题会导致耳聋和前庭障碍。揭示细胞的有用机制 周期调节可以提供从SC和/或剩余的HC产生新细胞的可能性， 提供诱导哺乳动物耳中HC再生的细胞基础。最近的研究提供了 两组疗法的原理证明：使用细胞周期蛋白系统或口袋蛋白基因（Rb 1）， 促进增殖，以及Atoh 1诱导SC向HC转分化（TD）的有效性。 结合起来，这两种方法可以模拟低等脊椎动物再生HC的能力。然而，在这方面， 除了原理证明之外，目前通过基因切除Rb 1来调节细胞周期的尝试并不 可能安全地重新填充丢失的HC和SC。对三个pRB成员Rb 1、Rb 11 （p107）和Rbl 2（p130）均在内耳中表达，并表现出广泛的免疫反应。 沿着沿着和穿过Corti器官彼此之间的差异和相似之处。删除任何pRB 使用各种条件和完全无效突变体，我们将 确定作为定量操作的固有比率的结果的SC增殖的能力， 在存在和不存在预先存在的HC的情况下，内耳感觉上皮中的pRB。这些 这些方法倾向于提供关于pRB操作在SC中的治疗适用性的见解 增殖和HC再生。