We are developing novel technologies to analyze important problems in biology. In addition, we are analyzing regulation mechanisms of the immune system by using the state-of-the-art transgenic/knock-out/knock-in technologies.
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| Figure 1. 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 signal-induced nuclear translocation of signaling proteins (Fig. 1) ITT is the first general technology to identify nuclear translocating proteins and enables us to analyze "translocatome", the entire set of nuclear translocating proteins in response to a defined extracellular stimulus. By using ITT, we will perform
(i) identification and characterization of signal-induced nuclear translocating proteins,
(ii) high-throughput screening of small compounds that affect nuclear translocation of signaling proteins, and
(iii) screening of RNAi library to identify proteins that regulate nuclear translocation of signaling proteins.
(2) We are developing the insertional chromatin immunoprecipitation (iChIP) system to isolate specific genomic regions that retain in vivo conformation. This system will enable us to perform non-biased molecular biological and biochemical analysis of their chromatin structure and to identify molecules (proteins, DNA, RNA, and others) that interact with the specific genomic regions of interest. By using iChIP, we perform biochemical and molecular biological analyses of specific genomic regions to elucidate molecular mechanisms of transcriptional regulation, cell differentiation, and lineage commitment, especially in the context of lymphocyte development.
II. Analysis of immune regulation mechanisms to develop treatments of autoimmune diseases
(1) We identified a novel phosphorylated nuclear protein, Cyclon, which is induced to express in T cells upon activation. We found that Cyclon regulates activation-induced cell death of T cells through modulating expression levels of Fas (Fig. 2). We attempt to analyze molecular mechanisms how Cyclon regulates Fas expression and analyze in vivo function of Cyclon by using transgenic and gene-deficient mice. We will make use of the knowledge obtained from the study to develop effective treatments of autoimmune diseases.
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| Figure 2. Normalization of splenomegaly in interleukin-2 receptor α-chain-deficient mice by transgenic expression of Cyclon. |
(2) We identified an activated T-regulatory cell (T-reg)-specific cell surface molecule, GARP, and showed that GARP plays an important role in immune suppression mediated by T-regs. We attempt to elucidate in vivo function of GARP by using transgenic and gene-deficient mice.