Characterising and targeting Cyclin D stabilisation in development and disease.

生物体以及大脑、手指和脚趾等器官的生长是通过细胞分裂发生的，并通过一系列精心调控的过程从简单的前体细胞转变为具有特定功能的复杂细胞。细胞周期通过要求细胞通过多个检查点来控制细胞分裂，以确保只有健康的细胞才能分裂。细胞的另一个重要能力是能够停止分裂。当发育中的大脑不需要更多的细胞时，细胞退出周期，导致产生的细胞不多于所需的细胞。未能退出细胞周期可能导致细胞数量过多，以及所谓的过度生长障碍，即器官太大，往往没有正确的结构。在大脑中，这导致了巨脑畸形。虽然大脑通常在完全发育后停止生长，但患有过度生长障碍的人的大脑会继续生长。这种生长即使在手术干预后仍然存在，导致进一步的并发症。有趣的是，在过度生长综合征中，一些患者还具有额外的手指和/或脚趾。综上所述，这些观察告诉我们，细胞周期的精确管理是大脑发育和肢体趾形成所必需的。本研究的目的是研究一个名为D型细胞周期蛋白（CCND）的蛋白质家族，该蛋白质家族充当细胞周期的分子开关。这将有助于理解控制细胞周期的分子过程，以及当它们不正常工作时，这些过程如何导致发育缺陷。当CCND水平高时，细胞继续分裂以产生更多的细胞，然而当CCND关闭时，细胞停止分裂。我感兴趣的是CCND 2没有被关闭的疾病，这意味着细胞继续分裂，即使它们不应该分裂。特别是，我想更多地了解控制这种开关的分子，当开关无法关闭时细胞中会发生什么，并开发克服高水平CCND 2的分子以阻止细胞分裂。利用这些信息，我希望了解细胞如何发出信号来正常停止细胞分裂，从而了解它们如何协调大脑等复杂结构的发育。目前还没有治愈或治疗方法可以克服CCND 2稳定的产后影响。在某些情况下，尝试手术，但成功有限。与CCND 2一样，其他D型细胞周期蛋白（如细胞周期蛋白D1）在无法关闭时也会导致疾病，如乳腺癌。通过对细胞周期调控机制的新见解，我的目标不仅是确定导致这些疾病的新疾病基因并了解它们所起的作用，而且还开发新的治疗方法，以改善患者及其家人的生活质量。

The growth of organisms, and organs such as the brain, fingers and toes, occur by cells dividing and changing from simple precursors into complex cells with specific functions through a series of carefully regulated processes. The cell cycle controls cell division by requiring the cell to pass multiple checkpoints to ensure only a healthy cell can divide. Another important ability for a cell is to be able to stop dividing. When no more cells are required in the developing brain, cells exit the cycle resulting in no more cells being produced than are needed. Failure to exit the cell cycle can lead to excessive cell numbers, and so-called overgrowth disorders, whereby organs are too big and often do not have the correct structure. In the brain this results in the disorder megalencephaly. While brains generally stop growing once fully developed, the brains of people with overgrowth disorders continue to grow. This growth persists even after surgical intervention, resulting in further complications. Interestingly in over-growth syndromes, some patients, also have an extra finger and/or toe. Taken together, these observations tell us that precise management of the cell cycle is required for development of the brain and formation of limb digits.The aim of this study is to investigate a family of proteins called D-type Cyclins (CCND), which act as a molecular switch for the cell cycle. This will help to understand the molecular processes that control the cell cycle and how these lead to developmental defects when they don't work correctly. When CCND levels are high, cells continue to divide to create more cells, however when CCND is switched off the cells stop dividing. I am interested in disorders that occur which CCND2 does not get switched off, meaning cells continue to divide even when they're not supposed to. In particular, I want to learn more about the molecules that control this switch, what happens in a cell when the switch cannot be turned off and to develop molecules that overcome high levels of CCND2 in order to stop the cells dividing. Using this information, I hope to learn how cells signal to stop cell division normally and therefore how they coordinate the development of complex structures such as the brain. Currently there are no cures or therapies available that can overcome the post-natal effects of CCND2 stabilisation. In some cases surgery is attempted, but with limited success. As well as CCND2, other D-type Cyclins such as Cyclin D1 also cause disease, such as breast cancer, when they cannot be switched off. By gaining new insights into the mechanisms governing the cell cycle, my aim is to not only identify new disease genes which cause these conditions and understand the roles they play, but also develop novel treatments in order to improve the quality of life for patients and their families.