Role of inflammation on craniofacial morphogenesis

唇腭裂是世界范围内最常见的先天性颅面畸形，对儿童及其家庭有毁灭性的影响。遗传学研究表明，细胞黏附分子E-钙粘附素的下调与一些口腔裂家族有关，而流行病学研究则将母体感染和母体发烧与子代的口腔裂伤联系起来。有趣的是，有证据表明E-钙粘附素的下调是由胃癌的炎症引起的。综上所述，我们提出了这样的观点，即在胚胎发育过程中激活的促炎因子会导致E-钙粘附素的抑制，而E-钙粘附素是正常颅面发育所必需的。正常的颅面发育主要依赖于头神经脊细胞的发育，头神经脊细胞是从头部后面向前面迁移的胚胎细胞群。口裂与头神经脊移移问题有关。间接证据表明，E-钙粘素是正常神经脊迁移所必需的，但这一点从未进行过直接测试。我们在两栖动物胚胎上的初步实验表明，炎症的诱导会导致E-钙粘蛋白的下调和神经脊迁移的损害。在这个项目中，我们将分析在诱导促炎反应后，神经脊的迁移和E-钙粘蛋白的水平。我们的目的是确定炎症控制神经脊迁移的细胞和分子机制。该项目的结果将对人类健康产生广泛的影响，因为它们将有助于了解口腔裂隙畸形的产生，为未来的诊断和治疗开辟新的途径。

Oral clefts, such as cleft lip and/or palate, are the most common congenital craniofacial malformation worldwide, and they have devastating effects on children and their families. Genetic studies have indicated that downregulation of the cell adhesion molecule E-cadherin is linked to some oral cleft families, while epidemiological studies have associated maternal infections and maternal fevers to oral clefting in the offspring. Interestingly, evidence suggest that downregulation of E-cadherin is induced by inflammation in cancer gastric. Together, these observations lead us to propose the idea that pro-inflammatory factors activated during embryo development result in inhibition of E-cadherin which is required for normal craniofacial development.Normal craniofacial development depends mainly on the development of cephalic neural crest cells which is an embryonic cell population that migrates from the back to the front of head. Oral clefts have been associated with problems in cephalic neural crest migration. Circumstantial evidence suggests that E-cadherin is required for normal neural crest migration, but this has never been directly tested. Our preliminary experiments in amphibian embryo, an animal model ideally suited for neural crest migration studies, show that induction of inflammation leads to down regulation of E-cadherin and impairment of neural crest migration.In this project we will analyse neural crest migration and E-cadherin levels after inducing a pro-inflammatory response. Our aim is to identify the cellular and molecular mechanism by which inflammation controls neural crest migration. The results of this project will have wide implication in human health as they will contribute to understand the generation of oral cleft malformations, opening new avenues for diagnostic and therapies in the future.