Regulation of Mammalian Cochlear Regeneration by BMP4

BMP4 对哺乳动物耳蜗再生的调节

• 批准号: 7321091
• 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 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321091
• 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

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 several 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.

感音神经性耳聋影响近一半的50岁以上的成年人。感觉神经性耳聋 是由耳蜗中机械感觉细胞的累积损失引起的，感觉毛细胞， 在胚胎发生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，但允许这些动物再生的信号是未知的。 我们希望研究的信号，可能调节感觉毛细胞分化的出生后哺乳动物 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可以存活， 增殖并分化成感觉毛细胞。我们在这里显示，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是一种潜在的细胞周期进入负调节因子， 支持细胞。这个数据很重要，原因有几个：首先，BMP 4在两种细胞的耳蜗中表达， 鸟类和小鼠，虽然在不同的人群;第二，BMP 4是下调，在再生鸟类 耳蜗，但可能不是在哺乳动物。因此，我们的模型提供了一个简单而可检验的假设， 鸟类可以再生，但哺乳动物不能。我们提出实验来确定的机制， 哪些BMP 4可能抑制增殖，BMP 4是否也在感觉毛细胞分化中发挥作用， 以及干扰BMP 4信号通路是否可以促进哺乳动物的再生。 体外耳蜗。 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，我们认为这一过程是由一种分子调控的 称为BMP 4。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。