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Aim
We aim to discover the phenomena that no one has ever seen before using fluorescence in vivo imaging techniques and to understand various pathological conditions using systems biology methods.
About FRET biosensors: See PHOGEMON Project
Keywords: Fluorescence live imaging, systems biology, cell biology, pathology, cancer, inflammation

SummaryThe rise and prosperity of molecular biology have led to the identification of a huge number of molecules that control intracellular signaling systems, the trend that continues to this day. Consequently, a very detailed and complex map of the signaling system has been created. However, these maps are often based on the dots of molecules and the lines of intermolecular interactions, lacking quantitative and qualitative information as well as spatio-temporal information. In order to breathe life into these maps, which have been accumulated through the efforts of many researchers, it is necessary to construct mathematical models based on measurement data that provide quantitative and qualitative information as well as spatio-temporal information as parameters. The same can be said for research at the individual or tissue level. Many important disease-related genes have been identified by genetic methods, and their molecular biological properties have been clarified; however, again, how the activity of these molecules is altered at the tissue level has remained largely unknown. We have created a number of fluorescent protein-based biosensors that can measure molecular activity in living cells, and have also created transgenic mice expressing these biosensors. In addition, we have created transgenic mice expressing these biosensors and established a system for real-time observation of molecular activity in living individuals for the first time in the world. With this unique technology, we aim to discover and understand phenomena that no one has ever seen before.

Our research strategy: Our laboratory started with the study of oncogenes and discovered several molecules related to the Crk oncogene signaling pathway in the 1990s. Low molecular weight G-protein activators represented by C3G (Crk SH3-binding guanine nucleotide exchange factor) and DOCK180 (Downstream of Crk, 180 kDA protein) are typical examples. Then, in 2001, we developed Raichu, the world's first fluorescent biosensor to visualize the activity of oncogenes, and since then we have created dozens of fluorescent biosensors. Since then, we have created dozens of fluorescent biosensors. We have succeeded in making the biosensors highly sensitive and stably expressed in cells and individuals, and in 2012, we succeeded in developing transgenic mice. These biosensors and transgenic mice are the technological core of our laboratory.

  • Reading the mind of cells: Cells, like humans, have states of joy, anger, sorrow, and pleasure. By observing live transgenic mice expressing fluorescent biosensors using two-photon excitation microscopy, we can read the "mind" of the cell and understand why the cell is activated and why it causes disease.
  • Manipulating cells: Observations always lead to a hypothesis, "This must be the case. To prove it, we need to show that we can manipulate the cells from the outside and get the expected results. For this purpose, we are developing tools to manipulate cells in living tissues.
  • Observing disease in living tissues: When transgenic mice expressing fluorescent biosensors are observed under a two-photon microscope, different cells show amazing expressions during various diseases. This is an exploratory project to find things that our predecessors have never seen before with new glasses. For example, we discovered the phenomenon of firework-like propagation of cell proliferation stimuli in skin tissue and named it SPREAD.

Movies
    Seeing molecular activities: Only One in the World

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