Analysis of the regulation and function of the mitotic kinase Citron kinase in cell division

有丝分裂激酶Citron激酶在细胞分裂中的调控及功能分析

基本信息

批准号：
BB/R001227/1
负责人：
Pier Paolo D'Avino
金额：
$ 51.15万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR001227%2F1
关键词：
Analysis regulation function mitotic kinase

项目摘要

Cells are the building blocks of many organisms, including humans. Growth, development and reproduction in all these organisms depend on the accurate and fascinating process of cell division, which faithfully partitions the genetic information between the two dividing cells. Proper cell division is also crucial for determining cell fate and tissue organization. Errors during this process are responsible for many genetic diseases, including Down's syndrome, microcephaly, sterility, and cancer. Thus, a thorough understanding of the mechanisms that control cell division may lead to the development of novel therapeutic treatments for these genetic diseases. Moreover, recent evidence also indicates a clear link between cell division and ageing and therefore a knowledge of the cell division process can help understand both the natural process of ageing and the origin of early ageing-related diseases. Complex control and surveillance mechanisms have evolved to ensure the fidelity and robustness of cell division. The genetic material - DNA - is compacted into chromosomes during cell division and is not accessible for the production of new factors. Therefore, the mechanisms that control cell division rely in large part on the regulation of the function and activity of proteins that have been generated before cells begin dividing. One class of proteins that play a key role in controlling the accuracy and fidelity of cell division are the serine/threonine kinases. These kinases can regulate the function, dynamics and activity of numerous other cell division proteins, known as substrates, by adding phosphate groups - a process know as phosphorylation - that alter the mechanical and structural properties of their targets. The goal of this project is to dissect the role of one of this kinase, Citron kinase (CIT-K), which controls different aspects of cell division. We propose to use cutting edge post-genomic technologies to identify all the substrates of CIT-K throughout cell division and to understand how CIT-K is itself regulated through phosphorylation by other kinases. As CIT-K has been linked to human primary microcephaly and proposed as a potential target in anti-cancer therapy, our research will not only help understand key mechanisms that control cell division and proliferation, but will also lay the foundation for the development of future therapies for the treatment of these human pathologies.

细胞是包括人类在内的许多生物的基础。所有这些生物的生长，发育和繁殖都取决于细胞分裂的准确而引人入胜的过程，这些过程忠实地将两个分裂细胞之间的遗传信息划分了。正确的细胞分裂对于确定细胞命运和组织组织也至关重要。在此过程中的错误导致许多遗传疾病，包括唐氏综合症，小头畸形，不育和癌症。因此，对控制细胞分裂的机制有透彻的理解可能导致这些遗传疾病的新型治疗治疗的发展。此外，最近的证据还表明，细胞分裂与衰老之间存在明确的联系，因此对细胞分裂过程的了解可以帮助了解衰老的自然过程和与早年相关疾病的起源。复杂的控制和监视机制已经发展为确保细胞分裂的忠诚度和鲁棒性。在细胞分裂期间，将遗传物质 - DNA-压实成染色体，无法用于生产新因素。因此，控制细胞分裂的机制很大程度上依赖于在细胞开始分裂之前已经生成的蛋白质功能和活性的调节。一类在控制细胞分裂的准确性和保真度中起关键作用的蛋白质是丝氨酸/苏氨酸激酶。这些激酶可以通过添加磷酸基团（称为磷酸化的过程）来调节许多其他细胞分裂蛋白（称为底物）的功能，动力学和活性，从而改变其靶标的机械和结构特性。该项目的目的是剖析该激酶之一Citron激酶（CIT-K）的作用，该激酶控制细胞分裂的不同方面。我们建议使用前沿基因组技术来识别整个细胞分裂中CIT-K的所有底物，并了解其他激酶通过磷酸化来调节CIT-K本身。由于CIT-K与人类原发性小头畸形有关，并提出是抗癌治疗的潜在靶标，因此我们的研究不仅将有助于了解控制细胞分裂和增殖的关键机制，而且还将为开发这些人类病理的未来疗法奠定基础。