Regulation of Mammalian Cochlear Regeneration by BMP4

BMP4 对哺乳动物耳蜗再生的调节

• 批准号: 7156178
• 负责人: Patricia M. White
• 金额: $ 9.05万
• 依托单位: HOUSE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-12 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7156178
• 关键词: Adult; Affect; Age; Alleles; Animals; BMP4; Biological Assay; Birds; Cell Culture System; Cell Cycle; Cell Death; Cell Differentiation process; Cell Proliferation; Cell division; Cells; Cochlea; DNA; Data; EGF gene; Embryo; Embryonic Development; Epithelial Cells; FGF2 gene; Fibroblast Growth Factor 2; Grant; Hair Cells; Hearing; Hour; In Vitro; Insulin; Labyrinth; Mammals; Mitogens; Mitosis; Mitotic; Modeling; Mus; Natural regeneration; Neonatal; Organ; Organ of Corti; Phase; Play; Population; Process; Proliferating; Regulation; Reporting; Role; Sensorineural Hearing Loss; Sensory Hair; Signal Pathway; Signal Transduction; Supporting Cell; System; Techniques; Testing; Thinking; Vertebrates; bone morphogenetic protein receptors; cell killing; daughter cell; deafness; extracellular; hair cell regeneration; loss of function; novel; receptor; recombinase; research study; transdifferentiation; vibration

DESCRIPTION (provided by applicant): Sensorineural deafness affects nearly half of adults over the age of 50. Primarily, sensorineural deafness is caused by the accumulated loss of mechanosensory cells in the cochlea, the sensory hair cells, which differentiate during embryogenesis and are not replaced. Adult non-mammalian vertebrates, in contrast, can regenerate lost sensory hair cells, but the signals that permit regeneration in these animals are unknown. We wish to investigate signals that may regulate sensory hair cell differentiation in the post-natal mammalian cochlea, using a novel in vitro system. In this system mouse embryonic cochlear epithelial cells can survive, proliferate, and differentiate into sensory hair cells. We show here as preliminary data that purified neonatal supporting cells have the ability to re-enter the cell cycle and express sensory hair cell markers in this assay. Through trial and error, we have identified BMP4 as a potential negative regulator of cell cycle entry by supporting cells. This data is important for two reasons: first, BMP4 is expressed in the cochleae of both birds and mice, although in different populations; second, BMP4 is down-regulated in the regenerating avian cochlea, but probably not in mammals. Thus, our model provides a simple and testable hypothesis for why birds might regenerate, but mammals do not. We propose experiments to determine the mechanism by which BMP4 might inhibit proliferation, whether BMP4 also plays a role in sensory hair cell differentiation, and whether interfering with the BMP4 signaling pathway might promote regeneration in the mammalian cochlea in vitro. People lose their hearing as they get older because the vibration-sensing cells in their inner ears die. Birds naturally regenerate their vibration-sensing cells, and we think this process is regulated by a molecule called BMP4. We want to test this idea by changing BMP4 activity in cultures of mouse inner ear organs.

描述（由申请人提供）：感觉性耳聋影响50岁以上的几乎一半的成年人。主要是，感觉性耳聋是由耳蜗中机械感觉细胞的累积丧失引起的，在胚胎发生过程中有分化的感觉毛细胞，而未能取代。相比之下，成年非哺乳动物脊椎动物可能会再生损失的感觉毛细胞，但是允许这些动物再生的信号尚不清楚。我们希望调查使用新型体外系统可以调节产后哺乳动物耳蜗中感觉毛细胞分化的信号。在这个系统中，小鼠胚胎耳蜗上皮细胞可以生存，增殖并分化为感觉毛细胞。我们在这里显示为初步数据，纯化的新生儿支撑细胞具有重新输入细胞周期并在此测定中表达感觉毛细胞标记的能力。通过反复试验，我们通过支持细胞将BMP4确定为细胞周期进入的潜在负调节剂。该数据很重要，原因有两个：首先，BMP4在鸟类和小鼠的耳蜗中表达，尽管在不同的人群中。其次，BMP4在再生的鸟类耳蜗中被下调，但可能没有在哺乳动物中。因此，我们的模型为鸟类为什么会再生的原因提供了一个简单且可检验的假设，但哺乳动物却没有。我们提出了实验来确定BMP4可以抑制增殖的机制，BMP4是否在感觉毛细胞分化中起作用，以及是否干扰BMP4信号传导途径是否会促进体外哺乳动物耳蜗的再生。人们随着年龄的增长而失去听力，因为内耳内部的振动感应细胞死亡。鸟类自然会再生其振动感的细胞，我们认为此过程受称为BMP4的分子调节。我们希望通过改变小鼠内耳器官培养物中的BMP4活性来测试这一想法。