Systematic molecular and cell biological analysis of MST kinase signalling in cell death cell cycle and centrosome biology

人体是由不同类型的细胞组成的，这些细胞具有特殊的任务。为了更好地理解细胞如何决定在哪里以及做什么，人们进行了大量的研究。最近的研究也表明，在正常的生理条件下，如发育或器官再生，理解细胞数量和组织结构是如何控制的是至关重要的。通常，为了确保每个组织不仅按照特定的结构而且按照定义的大小进行图案化，多细胞生物体通过严格的控制机制来管理细胞死亡和增殖的协调。因此，正在进行的研究的一个非常重要的方面是确定对这种协调至关重要的关键因素。有趣的是，通过特定标签(通过专家称为磷酸化的分子机制)修饰其他蛋白质的蛋白质有时在这些活动的协调中处于中心地位。这些修饰语(也称为Kinase)代表了我感兴趣的领域。值得注意的是，通过磷酸化标记蛋白质可以改变标记蛋白质的各种性质。例如，酶活性可以增加或减少，细胞内的定位可能改变，或结合伙伴可能丢失或获得。因此，非常重要的一点是，我们要了解如何严格调控激酶的活性。同样重要的是，我们还必须理解某些激酶活性的重要性(有时也是缺乏的)。在这项研究中，我将研究整个激酶家族尚未确定的复杂性。这个家族的成员已经被证明具有肿瘤抑制蛋白的功能，但我强烈认为，我们还没有揭示这些蛋白在健康的正常人类细胞中的重要功能。通过确定这些激酶在控制细胞如何死亡(程序性细胞死亡，也称为凋亡)和增殖(一种称为增殖的过程)中的作用，我将破译整个激酶家族的生物学意义。这些研究将涉及对激酶活性及其丰度水平的选择性操纵，以及使用额外的分子和细胞生物技术来确定哪些标记(磷酸化)事件是最重要的。总之，我强烈认为这项提案的主要目标将有助于提高我们对这个重要的激酶家族的理解。鉴于这些激酶在免疫和心血管系统以及肿瘤抑制中的作用，这项提案的发现可以作为改善终身健康和福祉的基础。从长远来看，了解这些激酶可能有助于确定这些蛋白在预防、检测、预测和治疗各种人类疾病中可以在多大程度上被用作读数。

The human body is composed of diverse cell types with specialised tasks. Much research has been carried out to gain a better understanding of how cells decide where to be and what to do. Recent research has also shown that it is crucial to comprehend how cell number and tissue architecture is controlled under normal physiological conditions such as development or organ regeneration. Normally, to ensure that each tissue is patterned not only to a specific architecture but also to a defined size, multicellular organisms govern the coordination of cell death and multiplication by strict control mechanisms. Therefore, one very important aspect of ongoing research is to define key factors that are essential for this coordination. Interestingly, proteins that modify other proteins by a specific tag (through a molecular mechanism called by specialists phosphorylation) are sometimes central in the coordination of these activities. These modifiers (also termed kinases) represent the field of my interest. Significantly, the tagging of proteins by phosphorylation can change various properties of the tagged protein. For example, enzymatic activities can be increased or decreased, the localisation within the cell might be altered, or binding partners might be lost or gained. Therefore, it is very important that we understand how the activity of kinases is strictly regulated. Equally important, we also must comprehend the importance of (or sometimes also the lack thereof) certain kinase activities. With this study, I will investigate the yet unidentified complexities of an entire family of kinases. Members of this family have already been shown to function as tumour suppressor protein, but I strongly believe that we are yet to unveil important functions of these proteins in healthy normal human cells. By identifying roles of these kinases in the control of how cells die (programmed cell death, also termed apoptosis) and multiplicate (a process termed proliferation), I will decipher the biological significance of the entire kinase family. The studies will involve performing selective manipulation of kinase activities as well as their level of abundance, and the use of additional molecular and cell biological techniques to define which tagging (phosphorylation) events are the most important. Altogether, I strongly feel that the main objectives of this proposal will help to improve our understanding of this essential kinase family. Given that these kinases function in the immune and cardiovascular system, as well as in tumour suppression, discoveries from this proposal could serve as a foundation for improvements regarding lifelong health and wellbeing. On the long-term, understanding these kinases might help to establish how far these proteins can be used as read-outs in the prevention, detection, prognosis and treatment of various human diseases.