先天性唇腭裂（CLP）是颌面部最常见的先天性发育畸形，非综合征性唇腭裂占其中70%，在我国发生率为1.82‰，造成患儿颌面畸形，严重影响患儿身心健康，对患者家庭和社会造成很大负担。其病因比较复杂，TGF-β信号通路是其中研究最多的通路之一，诱导性条件敲除小鼠是目前研究基因功能最为精确的模型之一。我们前期利用他莫昔芬在上皮诱导性条件敲除Tgfbr1（Tgfbr1 cKO）得到了一个不同于以往Tgfbr1条件敲除小鼠腭裂表型的腭裂模型，本课题将以此为基础，分别在组织学和细胞学层面研究TGF-β经典和非经典通路以及miRNA在Tgfbr1 cKO腭裂发生中的作用，并寻找其它相关基因，同时分析Tgfbr1对腭部间质细胞分化的影响，多角度的探讨Tgfbr1诱导性条件敲除小鼠腭裂发生的作用机制，从而增加对TGF-β通路的认识，扩大对唇腭裂发病机制的了解，进一步做好早期预防及诊断，进而减少唇腭裂的发生。

The most frequent birth defects of craniofacial abnormalities are the congenital cleft lip/palate(CLP). The majority of CLP (70%) are regarded as nonsyndromic, where the clefts occur without other anomalies. In China, occurrence of CLP estimates 1.82%, which results in complications affecting appearance, feeding, speech, hearing and psychological development. Patients and their families will undergo multiple rounds of surgical repair starting in the first year of life and may continue until 18 or 20 years old. Combined with multigenic inheritance and the influence of non-genetic factors, identifying the key genes in human CLP represents a major challenge. The TGF-β family is particularly interesting in palate development and isoforms 1, 2 and 3 are all expressed during this process. Altered TGF-β signaling causes syndromic and nonsyndromic cleft palate. Inducible conditional knockout mice models are one of the most accurate models to investigate gene function. Previously we generated a mutant animal model, in which tamoxifen inducible loss of Tgfbr1 in epithelium cells which is more accurately leads to cleft palate and is differed from previous cleft palate in Tgfbr1 conditional knockout mice model. Based on this mice model, we will investigate the molecular mechanism of TGF-β signaling-mediated palatogenesis by analyzing the role of TGF-β1,2,3 and the signaling downstream target genes both in SMAD-dependent and SMAD-independent in vivo and in vitro. As the role of miRNAs in craniofacial development is beginning to emerge, we will also investigate their roles in this mice model. And we will also investigate the role of Tgfbr1 during mouse embryonic palatal mesenchymal (MEPM) cells differ into muscle cells or osteogenic cells. The study of these genes and their molecular pathway will provide a useful and informative route with which to gain a better understanding of human CLP, and benefits of precise diagnosis, accurate risk assessment and genetic counseling can be achieved. And the potential for treatments and preventative therapies may also become a reality to reduce CLP.