Role of inflammation on craniofacial morphogenesis

炎症对颅面形态发生的作用

• 批准号: MR/W001292/1
• 负责人: Roberto Mayor
• 金额: $ 71.99万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW001292%2F1
• 关键词: Role; inflammation; craniofacial; morphogenesis

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.

口裂，如唇腭裂，是世界上最常见的先天性颅面畸形，它们对儿童及其家庭有毁灭性的影响。遗传学研究表明，细胞粘附分子E-钙粘蛋白的下调与一些唇裂家族有关，而流行病学研究则将母体感染和母体发热与后代的唇裂联系起来。有趣的是，有证据表明E-钙粘蛋白的下调是由胃癌中的炎症诱导的。总之，这些观察使我们提出这样的想法，即在胚胎发育过程中激活的促炎因子导致抑制E-钙粘蛋白，这是正常颅面发育所必需的。正常颅面发育主要取决于头神经嵴细胞的发育，头神经嵴细胞是一种从头部后部迁移到前部的胚胎细胞群。口裂与头神经嵴迁移问题有关。间接证据表明，E-钙粘蛋白是需要正常的神经嵴迁移，但这从来没有被直接测试。我们在两栖动物胚胎中的初步实验表明，炎症诱导导致E-cadherin的下调和神经嵴迁移的损害。在这个项目中，我们将分析神经嵴迁移和E-cadherin水平诱导后的促炎症反应。我们的目的是确定炎症控制神经嵴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影响，因为它们将有助于了解口裂畸形的产生，为未来的诊断和治疗开辟新的途径。

项目成果

Sculpting with stiffness: rigidity as a regulator of morphogenesis.

• DOI: 10.1042/bst20220826
• 发表时间: 2023-06-28
• 期刊: BIOCHEMICAL SOCIETY TRANSACTIONS
• 影响因子: 3.9
• 作者: Shellard, Adam;Mayor, Roberto
• 通讯作者: Mayor, Roberto

Cell-matrix and cell-cell interaction mechanics in guiding migration.

• DOI: 10.1042/bst20230211
• 发表时间: 2023-08-31
• 期刊: Biochemical Society transactions
• 影响因子: 3.9