p16INK4a in Cochlear Hair Cell Regeneration.

p16INK4a 在耳蜗毛细胞再生中的作用。

• 批准号: 8064638
• 负责人: Brandon C. Cox
• 金额: $ 5.05万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 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/8064638
• 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

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）损坏引起的。人类和其他哺乳动物不能取代受损的HCS；然而，鸡肉，鱼类和两栖动物可以通过相邻支持细胞的增殖和差异化（Conwin和Oberholtzer，1997）。有趣的是，非哺乳动物脊椎动物不存在肿瘤抑制基因P16INK4A，具有再生HCS的能力（Kim等，2003; Gil and Peters，2006）。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，1997）。众所周知，P16INK4A在包括神经元在内的成年细胞的体内再生能力中起关键作用（Janzen等，2006； Molofsky等，2006）。人们普遍认为，受损的HCS释放信号会导致SC重新进入细胞周期。在非哺乳动物脊椎动物中，这导致HC再生。但是，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，从而阻止了HC的再生。是否可以通过灭活p16Ink4a来给出鼠标的鼠标能够再生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的灭活将允许SCS：（1）响应受抗生素或遗传消融受损的HCS释放的信号，（2）重新进入细胞周期，并（3）再生HCS。为了检验该假设，我们提出了以下特定目的：具体目的1：确定由氨基糖苷抗生素庆大霉素引起的HC损伤后P161NK4A-NULL小鼠中SC的再生能力。具体目的2：确定在产后HC中急性失活引起的HC损伤后，p16INK4A-NULL小鼠中SC的再生能力。尽管哺乳动物不能自发再生HC，但HC再生的过程与非哺乳动物脊椎动物中发生的过程相似，可以通过耳蜗SC的遗传和/或治疗性操纵引起。该提案是朝着恢复暴露于耳毒性药物，大声噪音或其他环境药物的人的听力的最终目标的第一步。此外，在产后HCS中急性灭活视网膜细胞蛋白引起的HC损伤是该领域的技术突破。