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

PI 3-激酶亚型在自噬和内体膜动力学中的作用

• 批准号: G0700755/1
• 负责人: Bart Vanhaesebroeck
• 金额: $ 47.05万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700755%2F1
• 关键词: Roles; PI; kinase; isoforms; autophagy

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.

人体最基本的组成部分之一是称为细胞的结构。每一个细胞都被一层脂肪膜所包围，这层脂肪膜将细胞与周围环境隔离开来。此外，每一个细胞都被细分为更多的隔室，其中包含离散和独特的膜结合结构，称为细胞器。为了使细胞发挥功能，它必须能够执行许多角色，包括与细胞外环境的通信，细胞器之间的物质转移以及细胞自身内老化物质的再循环。这些功能中的任何一个缺陷都可能导致畸变，最终导致细胞功能障碍并导致癌症，即细胞的不受调节的生长。我们的实验室研究细胞内的催化剂，称为PI3Ks。PI3K能够特异性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的材料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突出表现在它们在高百分比的肿瘤中受到损害。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，那么我们必须了解PI3Ks在整个生物体中的功能。然而，这种调查途径的主要问题是，细胞内有许多PI3K的口味，每种口味在细胞内都发挥着不同的作用。为此，我们的实验室产生了小鼠模型，其中在细胞和整个生物体的水平上特异性地消除了离散PI3K的活性。通过这种方法，我们能够为每个PI3K分配特定的角色，并与制药公司结合设计针对每个PI3K的小分子抑制剂。然后在定向实验中测试这些小分子抑制剂，以确定它们是否在解决由缺陷PI3K信号传导引起的癌症和其他健康问题方面具有任何治疗用途。