Regulation of NF-kB by the ZO-1/ZONAB pathway

ZO-1/ZONAB 通路对 NF-kB 的调节

• 批准号: G0700743/1
• 负责人: Karl Matter
• 金额: $ 55.75万
• 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: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700743%2F1
• 关键词: Regulation; NF; kB; ZO; ZONAB

Epithelia are continuous layers of cells that delineate our tissues and organs. The integrity of epithelia is important for our organs to function normally and to protect us from our environment. For example, breaches in epithelial layers such as the skin or in the lining of the intestine can lead to serious infections. Individual epithelial cells interact with each other via molecular complexes that mediate adhesion but also function as sensors that transmit information about the environment, such as the presence or absence of neighbouring cells, to the cell interior. These sensors are important for the regulation of cell behaviour as they tell cells when to divide and when to stop to grow. If an epithelium is damaged, for example, cells divide and migrate to repair holes until they reach their neighbours and can form new adhesive complexes. Therefore, defects in these sensory mechanisms lead to severe diseases such as cancer. Many inflammatory diseases affect the functional properties of these adhesive molecular complexes. These diseases can be caused by bacteria and viruses, as well as allergens or by our own body defence system and often directly involve components of adhesive complexes. For example, a bacterium that causes gastric cancer injects molecules into epithelial cells that stimulate dissociation of adhesive complexes. Such infections also cause a cellular inflammatory response that helps our body to deal with them. However, these cellular responses can get out of control and cause damage. Here we focus on a new molecular mechanism by which adhesive complexes in epithelial cells can regulate the cellular inflammatory response. We propose to study the molecular mechanism and to determine how it is affected in two models of human disease. One model is based on the mentioned bacterium that causes gastric cancer and the other on cells isolated from colon and prostate cancers. Understanding how adhesive complexes guide the inflammatory response will help us to design new therapies for the above-mentioned diseases.

上皮细胞是连续的细胞层，描绘我们的组织和器官。上皮细胞的完整性对于我们的器官正常运作和保护我们免受环境影响非常重要。例如，上皮层（如皮肤）或肠道内层的破裂可能导致严重感染。单个上皮细胞通过介导粘附的分子复合物相互作用，但也作为传感器将有关环境的信息（例如相邻细胞的存在或不存在）传递到细胞内部。这些传感器对于调节细胞行为很重要，因为它们告诉细胞何时分裂，何时停止生长。例如，如果上皮细胞受损，细胞会分裂并迁移以修复孔洞，直到它们到达相邻的细胞并形成新的粘附复合物。因此，这些感觉机制的缺陷会导致严重的疾病，如癌症。许多炎性疾病影响这些粘附分子复合物的功能特性。这些疾病可以由细菌和病毒以及过敏原或我们自己的身体防御系统引起，并且通常直接涉及粘附复合物的成分。例如，导致胃癌的细菌将分子注入上皮细胞，刺激粘附复合物的解离。这种感染也会引起细胞炎症反应，帮助我们的身体处理它们。然而，这些细胞反应可能会失控并造成损害。在这里，我们专注于一个新的分子机制，粘附复合物在上皮细胞可以调节细胞的炎症反应。我们建议研究分子机制，并确定它是如何在两种人类疾病模型的影响。一种模型是基于上述引起胃癌的细菌，另一种是基于从结肠癌和前列腺癌中分离出的细胞。了解粘附复合物如何引导炎症反应将有助于我们设计针对上述疾病的新疗法。