We are developing novel technologies to address important questions in biology. In addition, we are analyzing mechanisms that regulate the immune system by using state-of-the-art transgenic/knock-out/knock-in technologies.
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| Figure 1.The inducible translocation trap system. |
I. Development of novel technologies to elucidate fundamental principles of the immune system
(1) We developed the inducible translocation trap (ITT) system to identify the signal-induced nuclear translocation of signaling proteins (Fig. 1). ITT is the first non-protein-specific technology that can identify nuclear-translocating proteins; it also enables the analysis of the "translocatome", namely the entire set of proteins that translocate to the nucleus in response to a defined extracellular stimulus. We will use ITT to
(i) identify and characterize signal-induced nuclear-translocating proteins,
(ii) perform high-throughput screening of small compounds that affect the nuclear translocation of particular signaling proteins, and
(iii) screen an RNAi library to identify proteins that regulate the nuclear translocation of signaling proteins.
(2) We are developing the insertional chromatin immunoprecipitation (iChIP) system to isolate specific genomic regions that retain their in vivo conformation. This system will enable us to perform unbiased molecular biological and biochemical analyses of the chromatin structure of specific genomic regions and to identify the molecules (proteins, DNA, RNA, and others) that interact with these regions. iChIP will also help us to elucidate molecular transcriptional regulation, cell differentiation, and lineage commitment mechanisms, especially those involved in lymphocyte development.
II. Analysis of immune regulation mechanisms and development of therapies for autoimmune diseases
(1) We identified a novel phosphorylated nuclear protein, Cyclon, whose expression is induced in T cells when they are activated. We found that Cyclon regulates the activation-induced cell death of T cells by modulating the expression levels of Fas (Fig. 2). We are currently using transgenic and gene-deficient mice to analyze the in vivo functions of Cyclon and the molecular mechanisms by which it regulates Fas expression. The knowledge generated by these studies will be used to develop effective therapies of autoimmune diseases.
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| Figure 2. Normalization of the splenomegaly in interleukin-2 receptor α-chain-deficient mice by the transgenic expression of Cyclon. |
(2) We identified GARP, an activated T-regulatory cell (T-reg)-specific cell surface molecule, and showed that it plays an important role in the immune suppression that is mediated by T-regs. We are currently elucidating the in vivo function of GARP by using transgenic and gene-deficient mice.