Regulation of Mammalian Cochlear Regeneration by BMP4

描述(申请人提供)：近一半50岁以上的成年人患有感觉神经性耳聋。首先，感觉神经性耳聋是由耳蜗区机械感觉细胞的累积损失引起的，这种感觉毛细胞在胚胎发育过程中分化，不能被取代。相比之下，成年非哺乳动物脊椎动物可以再生丢失的感觉毛细胞，但允许这些动物再生的信号尚不清楚。我们希望使用一种新的体外系统来研究可能调节出生后哺乳动物耳蜗内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存活、增殖并分化为感觉毛细胞。我们在这里展示了作为初步数据，纯化的新生儿支持细胞具有重新进入细胞周期的能力，并在本实验中表达感觉毛细胞标记。通过反复试验，我们已经确定BMP4是一种潜在的支持细胞进入细胞周期的负调控因子。这一数据之所以重要，有两个原因：第一，BMP4在鸟类和小鼠的耳蜗中都有表达，尽管在不同的种群中表达；第二，BMP4在再生的鸟类耳蜗中表达下调，但在哺乳动物中可能不表达。因此，我们的模型提供了一个简单且可检验的假设，解释为什么鸟类可以再生，而哺乳动物不能。我们建议进行实验，以确定BMP4可能抑制增殖的机制，BMP4是否也在感觉毛细胞分化中发挥作用，以及干扰BMP4信号通路是否可能在体外促进哺乳动物耳蜗组织的再生。随着年龄的增长，人们会失去听力，因为他们内耳中的振动感应细胞会死亡。鸟类会自然地再生它们的振动感应细胞，我们认为这个过程是由一种名为BMP4的分子调节的。我们想通过改变小鼠内耳器官培养中BMP4的活性来测试这一想法。

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.