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中文摘要：
听觉损伤可引起耳蜗毛细胞和听觉神经元的不可逆性损伤，从而导致永久性的感音神经性耳聋。虽然内耳所独具的结构是基因治疗非常独特和重要的靶器官，但能否实现损伤后毛细胞的再生是其前提条件。国内外研究者们做了大量的探索并取得重要突破，从非哺乳动物到哺乳动物毛细胞再生，从前庭毛细胞到耳蜗毛细胞再生，从未成熟期到成年期毛细胞再生，从离体培养毛细胞再生到在体毛细胞再生，整整经历了近半个世纪。但是毛细胞的再生并不等同于听力完全恢复。针对内耳基因治疗时间窗问题，我们根据听觉损伤后不同的病理状态，提出听觉损伤后毛细胞再生和基因治疗的基本策略：（1）毛细胞纤毛损伤阶段，是基因治疗的最好时机，通过完全修复或纤毛再生达到功能的完全或部分恢复；（2）内耳毛细胞虽有损伤但没有坏死，支持细胞和神经纤维基本正常，所以有恢复形态和功能的机会，这个阶段导入Math1基因应该有效，是基因治疗的最关键时机；（3）毛细胞严重损伤但支持细胞尚存，是毛细胞再生的抢救阶段，而且还可以争取在Corti器细胞构架没有塌陷之前进行干细胞导入，所以这个阶段内细胞移植可能有效地实现听力恢复；（4）Corti器完全失去构架，仅仅残留上皮层或瘢痕化，基因导入完全无效，即使干细胞导入也会面临困难,如何重塑Corti器构架是巨大挑战。为了实现耳聋基因治疗临床应用的可能性。我们还探索了最有效简便的外源基因内耳导入方式以及高效安全可靠的基因载体比如纳米载体的研发。毛细胞再生研究已经取得突破性进展，但还面临诸多挑战。通过不懈的努力，聋病基因治疗的最终临床应用一定会实现。
英文摘要：
Acoustic injury and ototoxic drags can leads to irreversible damage to cochlear hair cells and auditory neurons, and thus leads to permanent sensorineural hearing loss. Although inner ear is a very special and important target organ of gene therapy for its unique structure, it is necessary to generate new functional hair cells to restore hearing.Domestic and foreign researchers have done much exploration and have made significant breakthrough on hair cell regeneration, on which from non-mammal hair cells to mammal hair cells, from vestibular hair cells to cochlear hair cells, from immature hair cells to mature hair cells, and from in vitro hair cells to in vivo hair cells, on expending nearly a half century. However, hair ceils regeneration do not mean to fully hearing restoration. In order to solve the problems about time window of inner ear gene therapy, we have proposed the basic strategies of hair cell regeneration and gene therapy according to the different pathological states after hearing injury： （ 1 ） First stage when there is only hair cell cilia damage is the best chance for gene therapy, while the function can totally or partly restored through cilia fully repairing or regeneration; （2） Second stage when supporting cells and nerve fibers are normal but inner ear hair cell is injured but not necrosis is the most critical time for gene therapy. At this stage, Mathl gene transfer should be effective and it is possible that inner ear morphology and function can restore. （3） Third stage when hair cell is severely damaged but supporting cell still exists is the rescue phase of hair cell regeneration. What＇s more, we can manage to transfer stem cell before the structure of Corti＇s organ collapses so this phase is called rescue phase when cell replace or implantation can restore hearing effectively. 4. Four stage when Corti＇s organ lost its structure and only left epithelium or scar is totally useless phase for gene therapy and even stem cell implantation is also very difficult for reconstr
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Chondrocyte-specific Smad4 gene conditional knockout resulting in hearing loss and inner ear malform
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