Associations of receptors with membrane domains

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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.