Imprinted genes defining a novel growth regulatory axis

印记基因定义了新的生长调节轴

• 批准号: MR/S008233/1
• 负责人: Andrew Ward
• 金额: $ 58.92万
• 依托单位: University of Bath
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS008233%2F1
• 关键词: Imprinted; genes; defining; novel; growth; Imprinted; genes; defining; novel; growth

Correct growth during life in the womb is important for infant survival and is also known to impact health throughout life, including the risk of developing common metabolic disorders such as obesity, diabetes and heart disease. Growth is a highly regulated process but basic questions remain unanswered such as: How are appropriate body size and proportions achieved? Which genes are important and how do they link fetal growth with lifelong health? Through genetic studies in mice we have identified two genes involved in regulating fetal growth that also influence the balance of lean and adipose tissue in later life, along with other aspects of metabolic health. One of these genes, Dlk1, promotes fetal growth and limits adipose accumulation, whereas Grb10 restricts growth and promotes adipose deposition. We have strong evidence that the two genes influence these processes in opposite directions by acting antagonistically in the same regulatory circuit (or pathway). Such regulation, involving positive and negative factors to achieve fine control, is typical of biological systems. Our next goal is to identify other key components of the Dlk1/Grb10 pathway. Towards this aim, we have constructed a model of how the pathway might work, based on our own studies and those of others in the field. For instance, we know that while Grb10 directly inhibits growth, Dlk1 promotes growth indirectly by inhibiting Grb10. Also, quite a lot is known about the proteins encoded by the Dlk1 and Grb10 genes, from which we can infer the types of molecule they must interact with. In fact each interacts with different cell surface receptor molecules, akin to antennae projecting out from the cell membrane. Dlk1 encodes a signal protein released from one cell that interacts with receptors projecting from another. This type of cell to cell communication is important for coordinating the complex processes of growth and development. Grb10 encodes a molecule that interacts with receptors from within the cell, where it acts to modify how the cell responds to signals coming from the outside. In the case of Grb10 we have identified a strong candidate 'growth' receptor and one of our key goals is to validate and investigate this candidate further. Similarly, we have a candidate protein predicted to inhibit Grb10 as a consequence of Dlk1 signalling, and we will carry out experiments to test the interaction between the inhibitor and Grb10. These candidate molecules represent key components of the pathway, their validation would confirm important mechanisms predicted by our model and would provide the evidence needed to firmly establish the Dlk1/Grb10 growth axis. Finally, we have designed experiments that will enable us to discover additional pathway components, or alternatives should either of the candidates prove false. Our studies indicate that the pathway involving Dlk1 and Grb10 is novel and important for our understanding of fetal growth regulation. Further, knowledge of this pathway would impact the future development of advice and treatments to prevent growth and metabolic disorders.

子宫生活中的正确生长对于婴儿的生存至关重要，并且也会影响整个生命的健康，包括患有常见代谢疾病（例如肥胖，糖尿病和心脏病）的风险。增长是一个高度监管的过程，但基本问题仍未得到答复，例如：如何实现适当的身体大小和比例？哪些基因很重要？它们如何将胎儿生长与终身健康联系起来？通过小鼠的遗传研究，我们已经确定了两个与调节胎儿生长的基因，这些基因也影响了晚年瘦肉和脂肪组织的平衡，以及代谢健康的其他方面。这些基因之一DLK1促进了胎儿的生长并限制了脂肪的积累，而GRB10限制了生长并促进脂肪沉积。我们有强有力的证据表明，这两个基因通过在同一监管回路（或途径）中作用作用，以相反的方向影响这些过程。这种调节涉及实现良好控制的积极和负面因素，是生物系统的典型代表。 我们的下一个目标是确定DLK1/GRB10途径的其他关键组件。为了实现这一目标，我们根据我们自己的研究以及该领域的其他研究，构建了一个模型，说明了该路径的工作方式。例如，我们知道，尽管GRB10直接抑制生长，但DLK1通过抑制GRB10间接促进生长。同样，关于由DLK1和GRB10基因编码的蛋白质已经知道很多，我们可以从中推断出它们必须与之相互作用的分子类型。实际上，每种都与不同的细胞表面受体分子相互作用，类似于从细胞膜突出的天线。 DLK1编码从一个细胞释放的信号蛋白，该信号蛋白与另一个细胞相互作用的受体相互作用。这种类型的细胞与细胞通信对于协调复杂的生长和发育过程很重要。 GRB10编码与细胞内部与受体相互作用的分子，在该分子中，它可以修改细胞对来自外部的信号的反应。在GRB10的情况下，我们已经确定了强大的候选“生长”受体，我们的主要目标之一就是进一步验证和调查该候选人。同样，由于DLK1信号传导，我们预计有一种候选蛋白会抑制GRB10，我们将进行实验以测试抑制剂和GRB10之间的相互作用。这些候选分子代表途径的关键组成部分，它们的验证将确认我们的模型预测的重要机制，并提供牢固建立DLK1/GRB10生长轴所需的证据。最后，我们设计了实验，使我们能够发现其他途径组件，否则替代方案应证明是错误的。我们的研究表明，涉及DLK1和GRB10的途径对于我们对胎儿生长调节的理解很重要。此外，对这一途径的了解将影响未来的建议和治疗方法，以防止成长和代谢疾病。