Regulation of Mammalian Cochlear Regeneration by BMP4

描述（由申请人提供）：感音神经性耳聋影响近一半的50岁以上的成年人。首先，感觉神经性耳聋是由耳蜗中机械感觉细胞（感觉毛细胞）的累积损失引起的，该感觉毛细胞在胚胎发育期间分化并且不被替换。相反，成年非哺乳类脊椎动物可以再生失去的感觉毛细胞，但这些动物允许再生的信号尚不清楚。我们希望调查的信号，可能会调节感觉毛细胞分化的哺乳动物出生后的耳蜗，使用一种新的体外系统。在该系统中，小鼠胚胎耳蜗上皮细胞能够存活、增殖并分化为感觉毛细胞。我们在此显示作为初步数据，纯化的新生儿支持细胞具有重新进入细胞周期并在该测定中表达感觉毛细胞标志物的能力。通过反复试验，我们已经确定BMP 4作为支持细胞进入细胞周期的潜在负调节因子。这一数据很重要，原因有二：首先，BMP 4在鸟类和小鼠的耳蜗中都有表达，尽管在不同的种群中;其次，BMP 4在再生的鸟类耳蜗中下调，但在哺乳动物中可能没有。因此，我们的模型提供了一个简单而可检验的假设，解释为什么鸟类可以再生，而哺乳动物不能。我们提出的实验，以确定BMP 4可能抑制增殖的机制，BMP 4是否也在感觉毛细胞分化中发挥作用，以及是否与BMP 4信号通路的干扰可能促进再生在体外哺乳动物耳蜗。随着年龄的增长，人们会失去听力，因为内耳中的振动感应细胞死亡。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叫做BMP 4的分子调节的。我们想通过改变小鼠内耳器官培养物中BMP 4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.