器官损伤严重危害健康，但理论上可通过诱导组织的原位再生而简捷有效地加以修复；建立相关技术，是本次“重大研究计划”的一个目标。Wnt-b-catenin信号通路是调控细胞分裂、分化的常用开关，因而也是潜力巨大的药物靶点，但同时又是双刃剑，因为操纵不当，后果严重。因此，尽管经30多年的努力，20多种Wnt通路激动剂已经问世，但这些药物都缺乏足够的特异性并能自由扩散到非靶细胞，有明显的安全隐患，因此至今尚无一种获得FDA批准，这严重妨碍了再生医学的发展。本项目拟另辟蹊径，研发一种特异、高效、小巧、人源的RNA碱基编辑器，它能被选择性地表达在靶细胞中，通过消除b-catenin 磷酸化位点而特异性地激活Wnt通路；同时，拟结合自主研发、能高效感染耳蜗支持细胞的AAV，用小鼠听觉上皮的原位再生为模型，示范这一新型Wnt通路激动剂的医疗应用。本研究有助于突破再生医学的一个技术瓶颈，有明确的转化潜力。

Organ damages seriously jeopardize human health, but in theory could be readily repaired by inducing tissue regeneration in situ; establishing relevant technologies is a key objective of the current “Major Research Initiative”. The Wnt--catenin signaling pathway is a commonly used switch for controlling cell proliferation and differentiation, and hence a drug target with huge therapeutic potential in regenerative medicine. However, this pathway is also a double-edged sword, because its inappropriate intervention can produce devastating consequences. Over the past 30 years, more than 20 Wnt pathway agonists have been developed, but these agonists can unfortunately diffuse to non-target cells and/or impact irrelevant pathways unrelated to Wnt, and are thus fraught with safety concerns. As a result, none of them have been FDA-approved for clinical use, which has seriously hampered the progress of regenerative medicine. Here we will take a unique approach to counter the problem. First, we propose to develop a specific, efficient, small RNA base editor comprising proteins entirely of human origin; the editor can be selectively expressed in target cells, where it should specifically activate the Wnt pathway by removing the phosphorylation sites on b-catenin. Second, we propose to illustrate the medical applications of this novel Wnt pathway agonist using mouse auditory sensory epithelium regeneration as a model, which is made possible by an AAV we have previously developed that can efficiently deliver transgenes into cochlear supporting cells. Our study should help break a technical bottleneck in regenerative medicine, with clear translational potential.