Functional Characterization of Caveolae and Caveolins

该项目旨在研究细胞机制，使细胞能够对外部环境做出反应。具体来说，该项目侧重于膜蛋白家族的功能，称为小窝蛋白，它是覆盖在许多哺乳动物细胞表面的小窝的主要蛋白质成分。小窝蛋白被认为调节从外部环境到细胞内部的信号，这种调节的丧失会导致不受控制的生长，从而导致癌症。来自细胞表面的信号依赖于信号组件组成模块的组织。我们的研究表明，这些模块依赖于特定的脂质分子，这些脂质分子在细胞表面形成离散的斑块，称为脂筏。我们假设，小泡蛋白控制与脂筏相关的脂质分子，因此，间接地控制信号通路。特别是，我们已经证明了小窝蛋白在细胞胆固醇的调节中是重要的，而细胞胆固醇是维持脂质筏结构域功能的重要分子。由于许多人类疾病都与胆固醇失衡有关，对小窝蛋白的研究可以为这一过程以及之前未被发现的细胞脂质平衡和信号转导之间的联系提供基本的新见解。本项目旨在利用突变的小窝蛋白分子破坏小窝蛋白的功能，从而确定小窝蛋白在脂质调节和信号转导中的作用。然后，我们将使用一个易于实验操作的较低脊椎动物模型系统，以确定小洞蛋白和筏在整个胚胎发育中的作用。

This project aims to study the cellular machinery that allows a cell to respond to its external environment. Specifically, this project focusses on the function of a family of membrane proteins, called caveolins, which are the major protein components of caveolae small pits which cover the surface of many mammalian cells. Caveolins are believed to regulate signalling from the external environment to the cell interior and loss of this regulation leads to uncontrolled growth leading to cancer. Signalling from the cell surface relies on organisation of signalling components into modules. Our studies suggest that these modules are dependent on specific lipid molecules which form discrete patches, called lipid rafts, on the cell surface. We have hypothesised that caveolins control the lipid molecules associated with lipid rafts and so, indirectly, control signalling pathways. In particular, we have shown that caveolin is important in the regulation of cellular cholesterol, a vital molecule involved in maintaining the function of lipid raft domains. As numerous human diseases are associated with cholesterol imbalance, studies of caveolins can give fundamental new insights into this process, and the previously unidentified links between the cellular lipid balance and signal transduction. This project aims to use mutant caveolin molecules to disrupt caveolin function and so determine the role of caveolin in lipid regulation and in signal transduction. We will then use a lower vertebrate model system, which is amenable to experimental manipulation, to determine the role of caveolins and rafts in the development of the whole embryo.