As a result of the national projects in Japan, Dr Yasuda (Director, Department of Metabolic Disorder, Research Institute, IMCJ) and co-workers have recently reported for the first time that variants in KCNQ1 gene are strongly associated with susceptibility to type 2 diabetes mellitus. This accomplishment was achieved by The Study Group of Millennium Genome Project for Diabetes Mellitus, led by Dr Kasuga (Director General, Research Institute, IMCJ), which consisted of IMCJ and eleven core universities, in collaboration with National Cancer Center, RIKEN and other typing centers. An international meta-analysis revealed that this gene conferred susceptibility to the disease not only in East Asian populations but also in those of European descent. This work has been published in Nature Genetics（Yasuda et al. Nat Genet 40（9）:1092-1097, 2008）.

A monograph entitled “GIS and Malaria Surveillance” (Dec 2007: ISBN978-4-902358-04-9) was published as a product of collaborative researches mainly between Dept Approp Technol Dev Trans, Res Inst, IMCJ and Dept Parasitol, Coll Pub Hlth, Univ Philippines. The focused GIS study and surveillance are on those malarious provinces that were affected by natural disasters in the recent past. The study was partly supported by Grants from Ministry of Health Labour and Welfare of Japan (H18-Shinkou-Ippan-009).

Shiga toxin (Stx) is a major virulence factor of Stx-producing E. coli O157:H7. Stx has 15 potential receptor-binding sites and binds to target cells with high affinity through multivalent interactions. This is referred to as the “clustering effect.” We developed a novel technique that enables the identification of a compound which specifically inhibits the clustering effect. Using this technique, we identified a tetravalent peptide-compound that binds to Stx with high affinity and markedly inhibits Stx in vitro and in vivo. This technique is widely applicable to the development of selective inhibitors for a variety of disease-related molecules which exert the clustering effect.

The result was published in FASEB J. (published on line: K. Nishikawa et al.）

When DNA is damaged, ATM and H2AX proteins are phosphorylated and it stops cell proliferation (Fig. left). This is one of the natural cell protection systems. In HIV-1 patients, a high incidence of malignant tumor development has been observed, indicating DNA damage in this infection. The Departments of Intractable Diseases and Hematology have shown evidence that Vpr, an accessory gene product of HIV-1, causes DNA damage that involves ATM and H2AX phosphorylation. DNA fragility in HIV-1 infected cells may be related to HIV-1 associated malignancy.

The effect of HIV-1 Vpr induced DNA damage in viral infections, particularly in HIV-1 infection still remains to be solved. By solving these problems, new diagnostic method and hopefully new treatment strategy will be developed and will be able to contribute to improve patients' QOL.

(Nakai-Murakami C et al.Oncogene in press)

Parental grafts (MHC homozygous) are accepted in F1 (MHC heterozygous) recipients in organ transplantation. However, irradiated MHC heterozygous mice often reject bone marrow (BM) cells from the parents. This mysterious phenomenon differs from transplantation rules and is called "Hybrid resistance". Its molecular mechanism still remains unknown. Ogasawara and colleagues have shown that RAE-1 is involved in this phenomenon.

(Ogasawara et al)

Human embryonic stem cells (KhES-1) from Kyoto University were cultured on the Matrigel-coated dish in the serum free MEF-conditioned medium. Both small colony (Fig. 1) and large colony (Fig. 2) showed morphology of human embryonic stem cells with immature phenotype.

Elimination of the sialyl Lewis(x/a) from cancer cells has been an important goal for the control of cancer metastasis. Kawamura et al. in the Department of Gastroenterolofy provided evidence that the induction of Sd(a) blood group determinant by the action of a specific glycosyl-transferase, beta1,4N-acetyl-galactosaminyltransferase, efficiently eliminated sialyl Lewis(x/a) from cancer cells, reduced the E-selectin-mediated adhesion (Fig), and abolished metastasis in vivo.

With collaborators, the Department of Respiratory Diseases has released a booklet entitled “How to conduct international collaborative research in Vietnam -ver.1”. We expect this manual will help researchers conduct high-quality studies between Vietnam and Japan.

Department of Gene Diagnostics and Therapeutics has publicized database for metabolic diseases including cardiovascular disorders, with a large amount of SNPs information being compiled. On September 12, 2005, it has been updated to version 2, where a total of 401 genes (with 5914 SNPs) are deposited. We will develop it to become “integrated database” by adding the results for genetic analysis in metabolic diseases.

"A research on malaria prevention and treatment (H15-Shinkou-22)" has been conducted in the Department of Appropriate Technology Development and Transfer, under Health and Labour Sciences Research Grants from Ministry of Health Labour and Welfare, Japan. The booklet on the guidelines was published (March 2005: ISBN4-434-06047-3) as a product of the research, which has already been carefully read by medical practitioners in Travel Clinic in IMCJ, National Hospital Organization, quarantine offices, JICA clinics, Japanese Embassies world wide, and private clinics in Japan.

Cellular elements in CDDP-resistant cells (RES) were analyzed by scanning X-ray fluorescence microscopy, which is set up at an undulator beamline, BL29XL of the Spring-8 synchrotron radiation facility by combining a Kirkpatrick-Baez-type X-ray focusing system. RES showed significant amount of Zn concentration, which has highly correlated with glutathione, one of the major excretion systems. Controlling cellular Zn is proposed as a novel cancer treatment in RES, since Zn chelator down-regulated glutathione and enhanced CDDP-sensitivity.

(Cancer Research, 2005, 65:4998-5002)

Autoimmune diabetes is caused by immunological attack on the pancreatic cells by autoreactive T cells that respond to the cells of our own boty. The precise molecular mechanism, however, has been unknown. Dr. Ogasawara K, Head of Division of Clinical Immunology of this institute found that autoreactive T cells express a receptor called NKG2D in the pancrease. When he blocked NKG2D function by antibody, autoimmune diabetes was suppressed in 100% of cases (Ogasawara K et al). For these publications, he was given an HFSP Career Development Award by Minister of Education, Culture, Sports and Technology. His scientific accomplishments have been reported by many scientific journals and news media.

・Nature Medicine, News & Views “Type I diabetes: focus on prevention”
・Nature Reviews, Highlights "NKG2D receptor: a therapeutic target?"
・Reuters (USA, UK) “Anti-NKG2D Antibody Prevents Autoimmune Diabetes in Mouse Model”　and 10 other reports

Intestinal tissue repair after irradiation was delayed in IL-4 receptor gene deficient mice. The pictures show the small intestine 3 days after gamma-irradiation. IL-4 receptor gene deficient mice did not show transient upregulation of IL-13 receptor α2, which was seen in wild type mice. We injected soluble form of IL-13 receptor α2, to IL-4 receptor gene deficient mice, which resulted in increased number of dividing cells and improvement of epithelial regeneration. Further, treatment with soluble IL-13 receptor α2 promoted regeneration of epithelial cells in the intestine of WT mice after severe damage induced by 12-Gy irradiation. The IL-13 receptor α2 is a major regulatory factor involved in the regeneration of epithelial cells in the GI tract. (Gastroenterology, in press)