Associations of receptors with membrane domains

当体内的细胞进行交流时，它们使用一系列中间分子(配体)，这些分子(配体)被反应细胞表面的特定蛋白质分子(受体)识别。这些受体相互作用，在细胞内产生信号，导致细胞激活、分裂、改变或死亡。这一建议旨在了解受体分子如何在膜内相互作用，引起一种特定的反应，而不是另一种。潜在的假设是，受体分布在细胞表面的特定区域中，这种分布使细胞易于以特定的方式做出反应。具体的建议是使用相关光谱的共聚焦显微镜图像分析，来确定在接触配体之前、暴露期间和之后，哪些受体与细胞表面的哪些区域相关。此外，我们想要确定受体是否从一个区域移动到另一个区域以及如何移动。最后，我们建议确定受体的相互作用是直接的分子接触还是通过其他分子的间接联系。为了实现这一点，我们计划使用之前在实验室开发的图像相关光谱工具，并将其应用扩展到直接在活细胞中研究分子相互作用。我们特别建议研究两个蛋白质受体系统：骨形态发生蛋白受体和表皮生长因子受体。前者参与导致骨形成(成骨细胞)或骨降解(破骨细胞)的细胞的发育，因此，如果我们能够了解它们如何调节这种平衡，我们可能会更多地了解如何控制骨质疏松症和植入骨骼后的骨形成(成骨)问题。后者参与表皮细胞的生长，并已被用作跨膜受体的模型系统已有20年。因此，它将成为其他受体系统的有用的比较对象。

When cells in the body communicate, they use a series of intermediate molecules (ligands) that are recognized by specific protein molecules (receptors)on the surface of the responding cell.  These receptors interact among each other and create a signal within the cell that leads the cell to get activated, divide, change or die.  This proposal is aimed at understanding how the receptor molecules interact within the membrane to cause one specific response rather than another.  The underlying hypothesis is that the receptors are distributed in special domains on the surface of the cell and that this distribution predisposes the cell to respond in a particular way.  The specific proposal is to use confocal microscope image analysis by correlation spectroscopy to determine which receptors are associated with which domains on the surface prior to exposure to the ligand, during exposure and afterwards.  Further, we want to determine whether receptors move from one domain to another and how.  Finally, we propose to determine whether the receptor interactions are direct molecular contacts or indirect through other molecules.  To achieve this, we plan to use image correlation spectroscopy tools developed previously in the lab and to extend their application to study molecular interactions directly in the living cell. We propose specifically to study two protein receptor systems: the bone morphogenetic protein receptors and the epidermal growth factor receptors.  The former are involved in development of cells that cause either bone formation (osteoblasts) or bone degradation (osteoclasts) so if we can learn how they regulate this balance, we may learn more about how to control diseases such as osteoporosis and problems of bone formation (ossification) following insertion of implants in bones.  The latter are involved in growth of epidermal cells and has been used as a model system for transmembrane receptors for two decades.  It will therefore serve as a useful comparitor for other receptor systems.