Roles of PI 3-kinase isoforms in autophagy and endosomal membrane dynamics

人体最基本的组成部分之一是一种被称为细胞的结构。每个细胞都被一层脂肪膜包围着，这层膜使它的身份与周围环境分开。此外，每个细胞被自身细分为更多的隔室，其中包含离散的和独特的膜结合结构，称为细胞器。为了让细胞发挥功能，它必须能够发挥许多作用，包括与细胞外环境的沟通，细胞器之间的有规律的物质转移，以及细胞本身内陈旧物质的循环利用。这些功能中的任何一种缺陷都可能导致失眠，最终导致细胞功能障碍，并导致癌症，即细胞的不受调控的生长。我们的实验室研究电池内的催化剂，称为PI3K。PI3K能够特定地操纵细胞膜的组成。这些操作对于确保细胞器之间以及外部环境与细胞器之间物质转移的保真度至关重要。这些PI3K在维持正常细胞功能方面的重要性因它们在高比例的肿瘤中受损的事实而突显出来。因此，很明显，如果我们希望解决癌症的原因，并试图治愈癌症患者，我们知道PI3K在整个生物体中的功能是至关重要的。然而，这种研究途径的主要问题是，细胞内存在多种类型的PI3K，每种类型在细胞内扮演着不同的角色。为此，我们的实验室建立了小鼠模型，在该模型中，离散的PI3K的活动被特定地消融，无论是在细胞水平还是整个生物体水平。通过这种方法，我们能够为每个PI3K分配特定的角色，并结合制药公司设计针对每个PI3K的小分子抑制剂。然后，这些小分子抑制剂在定向实验中进行测试，以确定它们在治疗癌症和其他由PI3K信号缺陷引起的健康问题方面是否有任何治疗作用。

One of the most fundamental component parts of the human body is a structure termed a cell. Every cell is surrounded by a membrane of fat which maintains its identity separate from the surrounding environment. Furthermore, every cell is subdivided into more compartments by itself containing discrete and unique membrane-bound structures termed organelles. In order for a cell to function it must be able to perform a number of roles including communication with the extracellular milieu, the regulated transfer of material between organelles and the recycling of aged material within the cell itself. Defects in any of these functions can lead to abberations which ultimately cause the cell to malfunction and lead to cancer, the unregulated growth of cells. Our laboratory works on catalysts within the cell termed PI3Ks. PI3Ks are able to specifically manipulate the composition of the cellular membranes. These manipulations are critical to ensure fidelity of the transfer of material between organelles and between the external environment and organelles. The importance of these PI3Ks in maintaining normal cellular functions is highlighted by the fact that they are compromised in a high percentage of tumors. Consequently it is obvious that if we wish to tackle the causes of cancer and try to cure patients suffering from cancer it is vital that we know how PI3Ks function in whole organisms. The main problem with this avenue of enquiry however is that there are numerous flavors of PI3K within cells and each performs a distinct role within the cell. To this end our laboratory generate mice models where the activity of discrete PI3Ks are specifically ablated, both at the level of cells and the whole organism. By this methodology we are able to assign specific roles to each PI3K and in combination with drug companies design small molecule inhibitors targeted towards each PI3K. These small molecule inhibitors are then tested in directed experiments to see whether they will be of any therapeutic use in tackling cancer and other health issues arising from defective PI3K signalling.