Integration of cell-cell interactions and cell division by novel Dkk1 functions

通过新颖的 Dkk1 功能整合细胞间相互作用和细胞分裂

• 批准号: BB/V015362/1
• 负责人: Corinne Houart
• 金额: $ 80.28万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV015362%2F1
• 关键词: Integration; cell; interactions; division; novel

Cells connect to each other by forming cell-cell contacts, or adhesions, between neighbouring cells. These adhesions are essential for maintaining tissue integrity and for communication between cells. When intercellular adhesion is compromised, cells may break free from their neighbours and become invasive, or cells relying on close contact for signal transmission, such as nerve cells, may lose their ability to signal between neighbouring cells. The consequence of such events is often associated with human disease. Our research is centered on a molecule called Dkk1, a secreted protein that induces head formation during embryonic development. Dkk1 is frequently detected in several cancers with elevated levels correlating with disease progression and a poor prognosis, and is also associated with loss of signalling between nerve cells, called synaptic signalling, which is linked to Alzheimer's disease. The functional role of Dkk1 in these diseases is unresolved. Using the zebrafish embryo as an in vivo model, we have recently reported that Dkk1 disrupts migration of groups of cells in the embryo due to reduced cell-cell adhesion, and that this occurs by a mechanism different from its known signalling function. We now propose to carry out experiments to gain insight into how Dkk1 reduces cell-cell adhesion by identifying interaction partners in vivo and study how they contribute to Dkk1's function in regulation of cell adhesion and cell behaviour. We have also found a pool of Dkk1 associated with structures that orchestrate cell division, which we propose to also further investigate. Insight into the mechanisms by which Dkk1 impacts cell behaviour and cell division will be crucial for understanding Dkk1's role in cancer and neurodegenerative disease.

细胞通过在相邻细胞之间形成细胞细胞触点或粘连来相互连接。这些粘附对于维持组织完整性和细胞之间的通信至关重要。当细胞间的粘附受到损害时，细胞可能会从邻居中脱离并变得侵入性，或者依靠密切接触信号传播的细胞（例如神经细胞）可能会失去其在相邻细胞之间发出信号的能力。此类事件的后果通常与人类疾病有关。我们的研究集中在一个称为DKK1的分子上，DKK1是一种分泌的蛋白质，可在胚胎发育过程中诱导头部形成。在几种与疾病进展和预后不良相关的癌症中，经常检测到DKK1，并且与神经细胞之间的信号丧失（称为突触信号传导）有关，这与阿尔茨海默氏病有关。 DKK1在这些疾病中的功能作用尚未解决。使用斑马鱼胚作为体内模型，我们最近报告说，由于细胞细胞粘附的降低，DKK1破坏了胚胎中细胞组的迁移，并且这是通过与其已知信号函数不同的机制发生的。现在，我们建议进行实验，以深入了解DKK1如何通过鉴定体内的相互作用伴侣来降低细胞 - 细胞粘附，并研究它们如何促进DKK1在调节细胞粘附和细胞行为方面的功能。我们还发现了与编排细胞分裂的结构相关的DKK1池，我们建议这也进一步研究。对DKK1影响细胞行为和细胞分裂的机制的洞察对于了解DKK1在癌症和神经退行性疾病中的作用至关重要。