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）：感音神经性耳聋影响近一半的 50 岁以上成年人。感音神经性耳聋主要是由耳蜗中机械感觉细胞（感觉毛细胞）的累积损失引起的，这些细胞在胚胎发生过程中分化并且不会被替换。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型体外系统来研究可能调节产后哺乳动物耳蜗中感觉毛细胞分化的信号。在该系统中，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记的能力。通过反复试验，我们发现 BMP4 是支持细胞进入细胞周期的潜在负调节因子。该数据很重要，原因有两个：首先，BMP4 在鸟类和小鼠的耳蜗中都有表达，尽管在不同的群体中；其次，BMP4 在再生鸟类耳蜗中下调，但在哺乳动物中可能不会。因此，我们的模型为为什么鸟类可能再生而哺乳动物却不能再生提供了一个简单且可检验的假设。我们提出实验来确定 BMP4 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 信号通路是否可能促进哺乳动物耳蜗的体外再生。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叫做 BMP4 的分子调节的。我们希望通过改变小鼠内耳器官培养物中 BMP4 的活性来测试这个想法。