Regulation of cochlea hair cell differentiation by the Lin28b/let-7 axis

描述(申请人提供)：声音感知是通过由机械感觉毛细胞和支持细胞组成的特殊感觉上皮来调节的。这种上皮细胞的正常发育和维持对听力至关重要，而这些细胞的丧失会导致耳聋。虽然包括鸟类和爬行动物在内的许多脊椎动物能够再生受损的毛细胞，但哺乳动物(包括人类)没有保留这种能力，导致受伤后永久耳聋。基因治疗是一种潜在的有希望的治疗干预措施，有朝一日可能允许聋人听力的恢复。然而，在开发靶向基因表达的治疗方法之前，必须首先了解这些感觉细胞产生的分子机制。这项研究的长期目标是揭示调控哺乳动物发育中毛细胞分化的分子机制。我们的实验室已经发现了异时的Lin28b/let-7轴在耳蜗分化过程中表达，并与毛细胞分化的开始重叠。在包括线虫和小鼠胚胎干细胞在内的其他模式生物的研究中，已经发现了这个轴在调节发育进程和分化方面的重要性。在这项研究中，我们将使用成熟的遗传工具，包括小鼠转基因和逆转录病毒介导的基因传递，在耳蜗感觉上皮分化过程中干扰Lin28b/let-7轴的表达。利用分子和细胞生物学技术，我们将确定破坏这一途径对毛细胞分化和成熟的影响。我们希望，这项提案中提出的实验将 促进我们对耳蜗感觉细胞发育和维持的遗传机制的理解。

DESCRIPTION (provided by applicant): Sound perception is mediated through a specialized sensory epithelium made up of mechanosensory hair cells and supporting cells. The proper development and maintenance of this epithelium is critical for hearing, and loss of these cells leads to deafness. While many vertebrates, including birds and reptiles, are able to regenerate damaged hair cells, mammals (including humans) do not retain this ability, resulting in permanent deafness after injury. Gene therapy is a potentially promising therapeutic intervention that may one day allow for the recovery of hearing in deaf individuals. However, before therapies that target gene expression can be developed the molecular mechanisms that underlie the generation of these sensory cells must first be understood. The long-term goal of this study is to uncover the molecular mechanisms regulating the initiation of hair cell differentiation in the developing mammalian cochlea. Our lab has found the heterochronic Lin28b/let-7 axis to be expressed during cochlea differentiation, overlapping with the onset of hair cell differentiation. Studies in other models organisms including C. elegans and mouse embryonic stem cells have uncovered the importance of this axis in regulating developmental progression and differentiation. In this study we will use well-established genetic tools, includin mouse transgenics and retroviral-mediated gene delivery, to disrupt the expression of the Lin28b/let-7 axis during cochlea sensory epithelium differentiation. Using molecular and cellular biological techniques we will determine the effects of disrupting this pathway on hair cell differentiation and maturation. It is our hope that the experiments put forth in this proposal will advance our understanding of the genetic mechanisms underlying the development and maintenance of sensory cells in the cochlea.