p16INK4a in Cochlear Hair Cell Regeneration.

p16INK4a 在耳蜗毛细胞再生中的作用。

基本信息

批准号：
7753757
负责人：
Brandon C. Cox
金额：
$ 4.72万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753757
关键词：
Ablation Acute Adult Age Aminoglycoside Antibiotics Amphibia Animals Antibiotics CDKN2A gene Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cells Cellular Morphology Chickens Cochlea Cyclin-Dependent Kinase Inhibitor Diuretics Ethacrynic Acid Event Exposure to Fishes Genetic Gentamicins Goals Hair Cells Hearing Hematopoietic stem cells Human Knockout Mice Labyrinth Mammals Measures Mitotic Activity Mus Natural regeneration Neurons Noise Pharmaceutical Preparations Phosphorylation Platinum Play Process Retinoblastoma Retinoblastoma Protein Role Sensory Hair Signal Transduction Site Supporting Cell Techniques Testing Therapeutic Tumor Suppressor Genes Tumor Suppressor Proteins Vertebrates Work adult neurogenesis base cell injury chemotherapy environmental agent hair cell regeneration hearing impairment in vivo juvenile animal novel olfactory bulb postnatal prevent regenerative subventricular zone transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Hearing loss is primarily caused by damage to sensory hair cells (HC) in the cochlea of the inner ear. Humans and other mammals cannot replace damaged HCs; however, chicken, fish and amphibians can, by proliferation and transdifferentiation of neighboring supporting cells (SC) (Conwin and Oberholtzer, 1997). Interestingly, the tumor suppressor gene, p16INK4a, is absent in non-mammalian vertebrates that have the capacity to regenerate HCs (Kim et al., 2003; Gil and Peters, 2006). In mammals, p16INK4a acts as a cyclin-dependent kinase inhibitor that keeps cells in a quiescent state. Its expression is induced by age as well as mitogenic signaling (Zindy et al., 1997). p16INK4a is also known to play a critical role in the in vivo regenerative ability of adult cells, including neurons (Janzen et al., 2006; Molofsky et al., 2006). It is commonly thought that damaged HCs release signals that cause SCs to reenter the cell cycle. In non-mammalian vertebrates this results in HC regeneration; however, in mammals, we predict that this mitotic activity induces the expression of p16INK4a which keeps SCs in a quiescent state and thus prevents HC regeneration. Is it possible to give a mouse, the chicken's ability to regenerate HCs by inactivating p16INK4a? To achieve this goal, we propose the following central hypothesis: Inactivation of p16INK4a in mammals will allow SCs: (1) to respond to signals released from HCs damaged by antibiotics or genetic ablation, (2) to reenter the cell cycle and (3) to regenerate HCs. To test this hypothesis, we propose the following specific aims: Specific Aim 1: To determine the regenerative capacity of SCs in p161NK4a-null mice after HC damage caused by the aminoglycoside antibiotic, gentamicin. Specific Aim 2: To determine the regenerative capacity of SCs in p16INK4a-null mice after HC damage caused by acute inactivation of the retinoblastoma protein in postnatal HCs. Although mammals cannot spontaneously regenerate HCs, a process of HC regeneration similar to what occurs in non-mammalian vertebrates could be induced by genetic and/or therapeutic manipulations of cochlear SCs. This proposal is the first step toward the final goal of restoring hearing in those exposed to ototoxic drugs, loud noise or other environmental agents. In addition, HC damage induced by acute inactivation of the retinoblastoma protein in postnatal HCs is a technological breakthrough for the field.

描述（由申请人提供）：听力损失主要是由内耳耳蜗中的感觉毛细胞（HC）损伤引起的。人类和其他哺乳动物无法替代受损的碳氢化合物；然而，鸡、鱼和两栖动物可以通过邻近支持细胞（SC）的增殖和转分化来实现（Conwin 和 Oberholtzer，1997）。有趣的是，肿瘤抑制基因 p16INK4a 在具有再生 HC 能力的非哺乳动物脊椎动物中不存在（Kim 等人，2003 年；Gil 和 Peters，2006 年）。在哺乳动物中，p16INK4a 充当细胞周期蛋白依赖性激酶抑制剂，使细胞保持静止状态。它的表达是由年龄和有丝分裂信号传导诱导的（Zindy 等人，1997）。众所周知，p16INK4a 在成体细胞（包括神经元）的体内再生能力中发挥着关键作用（Janzen 等，2006；Molofsky 等，2006）。人们普遍认为受损的 HC 会释放信号，导致 SC 重新进入细胞周期。在非哺乳动物脊椎动物中，这会导致 HC 再生；然而，在哺乳动物中，我们预测这种有丝分裂活性会诱导 p16INK4a 的表达，从而使 SC 保持静止状态，从而阻止 HC 再生。是否有可能通过灭活 p16INK4a 来赋予小鼠、鸡再生 HC 的能力？为了实现这一目标，我们提出以下中心假设：哺乳动物中 p16INK4a 失活将使 SC：（1）对抗生素或基因消融损坏的 HC 释放的信号做出反应，（2）重新进入细胞周期，（3）使 HC 再生。为了检验这一假设，我们提出以下具体目标：具体目标 1：确定 p161NK4a 缺失小鼠中 SC 的再生能力，该小鼠在氨基糖苷类抗生素庆大霉素引起的 HC 损伤后。具体目标 2：确定出生后 HC 中视网膜母细胞瘤蛋白急性失活导致 HC 损伤后 p16INK4a 缺失小鼠 SC 的再生能力。尽管哺乳动物不能自发地再生 HC，但通过对耳蜗 SC 进行遗传和/或治疗操作，可以诱导与非哺乳动物脊椎动物中发生的类似的 HC 再生过程。该提案是实现恢复接触耳毒性药物、噪音或其他环境因素的听力的最终目标的第一步。此外，出生后HC中视网膜母细胞瘤蛋白急性失活引起的HC损伤是该领域的技术突破。