Every cell in the human body must decide, moment by moment, whether to stick to its neighbours or move to a new location—and this project will map the atomic machinery that makes that decision possible. This matters because cells get their instructions from receptor molecules on their surface, which read signals from the surrounding environment. One key family of signals, the semaphorins, and their receptors, the plexins, control how cells adhere and migrate during development—for instance, when wiring the brain or building blood vessels. When these signals go wrong, the consequences can include failed nerve regeneration after spinal cord injury, bone disorders like osteoporosis, neurodevelopmental conditions such as autism, and cancer spread. Yet the atomic-level mechanics of how semaphorins and plexins actually work together remain unknown. This is fundamental science. The researchers will use structural biology techniques—producing purified samples of these molecules and their complexes, then studying them both in isolation and on the surface of living cells—to reveal the precise molecular choreography. There is no immediate therapeutic application. But understanding these basic mechanisms will give pharmaceutical and biotechnology industries the detailed knowledge they need to design drugs that could one day repair damaged nerves, correct developmental errors, or block cancer cell migration.
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The cells of a multicellular organism, such as a human, are subject to an exquisite choreography during development. Each cell must achieve the particular balance between adhesion and motility appropriate to its role at a specific time and place in the developing organism. Much of the information to direct each cell must be garnered through interaction with its immediate environment including neighbouring cells. These interactions are mediated by various types of receptor molecules embedded in the cell surface. We wish to understand how one family of molecules, the semaphorins, work together with their receptors, the plexins, to control the ability of a cell to stick (adhere) or to move in a specific direction. Using the techniques of structural biology we aim to uncover, in atomic detail, the mechanisms by which the semaphorins and plexins control cell adhesion and guidance, for example in directing the wiring of the brain. These mechanisms must integrate receptor interactions occurring between cells and on the same cell surface, as well as spanning from the extracellular to the intracellular environment. To generate insight into such systems we will need to use state of the art techniques to produce suitable samples of the semaphorins, the plexins and their complexes, and to combine in vitro structural studies on the isolated molecules with in situ analyses in the functionally relevant context of the cell surface. This is basic research into the mechanisms by which biology works to build the nervous system and the blood vessels, to maintain bones and to activate the immune system. By understanding these mechanisms we will also be better equipped to explore molecular factors which may contribute to the failure of severed nerves to regenerate following spinal cord injury, to bone-related disorders, for example osteoporosis, to neurodevelopmental disorders such as autism disorder spectrum, and to cancer. Ultimately this knowledge can be used by the biotechnology and pharmaceutical industries, to inform and guide the design of novel therapeutics.
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