Regulation of receptor signalling and ligand recognition by nanometer-scale membrane microdomains.

活细胞通过脂膜与其环境分离。 这些细胞膜不仅仅是简单的屏障，还具有将信息和营养物质传递到细胞中的能力，同时允许细胞向邻近细胞发出信号并输出废物。 信息和物质在这些膜上的流动取决于微区的形成-膜的局部区域包含支持一个信号，分子或力跨膜传输所需的所有蛋白质和脂质。 人们对这些微域的结构、形成和功能知之甚少，从而限制了我们理解这些微域调节的过程的能力。 这些领域的评估受到无法观察单个微区的技术的限制。 该提案将使用一种先进的显微镜形式，使我们能够突破传统显微镜的分辨率限制，来分析这些微区。 当与我的实验室最近开发的一种新的分析形式相结合时，这种先进的显微镜形式将使我们能够定量评估活细胞中这些微区的形成，结构和功能。 虽然这些微区是所有生物体（从简单的细菌到复杂的哺乳动物）的功能所必需的，但我们的研究将集中在哺乳动物细胞死亡期间形成的微区，以及在巨噬细胞膜中形成的微区通过称为“巨噬细胞增殖”的过程去除这些死亡和垂死的细胞。 通过采用这种方法，我们不仅将了解在所有形式的生命中调节这些结构域的形成和功能的基本物理和化学过程，而且我们还将揭示关于胞浆细胞增多症的功能和调节的重要信息-这是一个对包括人类在内的多细胞生物体的生存和健康至关重要的过程。

Living cells are separated from their environment by lipid membranes. These membranes are not just simple barriers, but also have the capacity to transmit information and nutrients into cells while simultaneously allowing the cell to signal to neighboring cells and export waste products. This flow of information and materials across these membranes is dependent on the formation of microdomains - localized regions of membranes containing all of the proteins and lipids necessary to support the transmission of one signal, molecule or force across the membrane. The structure, formation and function of these microdomains are poorly understood, thus limiting our ability to understand the processes regulated by these domains. Assessment of these domains has been limited by technologies incapable of observing individual microdomains. This proposal will use an advanced form of microscopy, which allows us to break past the resolution limits of conventional microscopy, to analyze these microdomains. When combined with a new form of analysis recently developed in my laboratory, this advanced form of microscopy will allow us to quantitatively asses the formation, structure and function of these microdomains in living cells. While these microdomains are required for the functioning of all living organisms, from simple bacteria through to complex mammals, our research will focus on the microdomains formed during the death of mammalian cells, and on the microdomains formed in the membranes of macrophages removing these dead and dying cells through a process termed 'efferocytosis'. By taking this approach we will not only learn about the basic physical and chemical processes which regulate the formation and function of these domains in all forms of life, but we will also uncover important information on the function and regulation of efferocytosis - a process critical to the survival and wellbeing of multicellular organisms including people.