Molecular Biomedicine for Pathogenesis

Molecular Biomedicine for Pathogenesis


Toru Miyazaki


Satoko Arai


Matsumi Maehara


Kaori Taniguchi

1. Research

New gene, New function, and New therapy

Our laboratory will focus on clarification of the pathogenesis of various diseases and the related physiological machineries in cellular and molecular aspects. Based on our technical advantage in gene manipulation via gene knockout and transgenesis, we will give high priorities to in vivo analyses. This will definitively contribute to the direct therapeutic application of our findings.
Since our rationale is to challenge to uncharacterized disease mechanisms and physiologies, we will not restrict our interest, strategy or technique employed, in certain specific field. Rather, we will expand our research area by establishing different collaborations with a broad spectrum of investigators. We believe this fits to the policy of the CDBIM, which aims the development of a comprehensive science including the fundamental and clinical medicines, and the biotechnology. Overall, we will attempt to discover novel biological insights rather than to study details of previously characterized physiologies, by targeting molecules newly identified by ourselves. The major specific aims during the next five years are as follows:

  1. Role of AIM (Apoptosis Inhibitor of Macrophage) in the development of metabolic syndrome.
  2. Regulation of hematopoiesis and its relevance to leukemogenesis;
    via functional analysis of a newly identified Polycomb group molecule MBT-1.
  3. Regulation of tumorgenesis by modulating apoptosis and cell cycle;
    via analysis of DEDD-deficient animals.

2. Publications

  1. Takahata, A., Arai, S., Hiramoto, E., Kitada, K., Makita, Y., Suzuki, H., Nakata, J., Araki, K., Miyazaki, T. & Suzuki, Y. Crucial role of AIM/CD5L in the development of glomerular inflammation in IgA nephropathy. Am. Soc. Nephrol. 31: 2013-2024 (2020).
  2. Hiramoto, E., Tsutsumi, A., Suzuki, R., Matsuoka, S., Arai, S., Kikkawa, M. & Miyazaki, T. The IgM pentamer is an asymmetric pentagon with an open groove that binds the AIM protein. Science Adv. 4: eaau1199 (2018).
  3. Koyama, N., Yamazaki, T., Kanetsuki, Y., Hirota, J., Asai, T., Mitsumoto, Y., Mizuno, M., Shima, T., Kanbara, Y., Arai, S., Miyazaki, T. & Okanoue, T. Activation of apoptosis inhibitor of macrophage is a sensitive diagnostic marker for NASH-associated hepatocellular carcinoma. Gastroenterol. 53: 770-779 (2018).
  4. Tomita, T., Arai, S., Kitada, K., Mizuno, M., Suzuki, Y., Sakata, F., Nakano, D., Hiramoto, E., Takei, Y., Maruyama, S., Nishiyama, A., Matsuo, S., Miyazaki, T. & Ito, Y. Apoptosis inhibitor of macrophage ameliorates fungus-induced peritoneal injury model in mice. Rep. 25: 6450 (2017).
  5. Kimura,, Suzuki, M., Konno, S., Shindou, H., Shimizu, T., Nagase, T., Miyazaki, T. & Nishimura, M. Orchestrating Role of Apoptosis Inhibitor of Macrophage in the Resolution of Acute Lung Injury. J. Immunol. 199: 3870-3882 (2017).
  6. Arai, S., Kitada, K., Yamazaki, T., Takai, R., Zhang, X., Tsugawa, Y., Sugisawa, R., Matsumoto, A., Mori, M., Yoshihara, Y., Doi, K., Maehara, N., Kusunoki, S., Takahata, A., Noiri, E., Suzuki, Y., Yahagi, N., Nishiyama, A., Gunaratnam, L., Takano, T. & Miyazaki, T. AIM/CD5L enhances intraluminal debris clearance and ameliorates acute kidney injury. Med. 22: 183-193, (2016).
  7. Wang, C., Yosef, N., Gaublomme, J., Wu, C., Lee, Y., Clish, C., Kaminski, J., Xiao, S., Meyer Zu Horste, G., Pawlak, M., Kishi, Y., Karwacz, K., Zhu, C., Ordovas, M., Madi, A., Wortman, I., Miyazaki, T., Sobel, R.A., Park, H., Regev, A. & Kuchroo, V.K. CD5L/AIM, a regulator of intracellular lipid metabolism, restrains pathogenicity of Th17 cells. Cell. 163: 1413-1427 (2015).
  8. Maehara, N., Arai, S., Mori, M., Iwamura, Y., Kurokawa, J., Kai, T., Kusunoki, S., Taniguchi, K., Ikeda, K., Ohara, O., Yamamura, K. & Miyazaki, T. Circulating AIM prevents hepatocellular carcinoma through complement activation. Cell Rep. 9: 61-74 (2014).
  9. Hamada, M., Nakamura, M., Thi Nhu Tran, M., Moriguchi, T, Hong, C., Ohsumi, T., Tra Thi Huong Dinh, Kusakabe, M., Hattori, M., Katsumata, T., Arai, S., Nakashima, K., Kudo, K., Kuroda, E., Wu, C.H., Kao, P.H., Sakai, M., Shimano, H., Miyazaki, T., Tontonoz, P. & Takahashi, S. MafB promotes atherosclerosis by inhibiting foam cell apoptosis. Commun. 5: 3147 (2014).
  10. Arai, S., Maehara, N., Iwamura, , Honda, S-I., Morita, K., Nakashima, K., Kurokawa, J., Mori, M., Motoi, Y., Miyake, K., Yamamura, K-I., Ohara, O., Shibuya, A., Wakeland, E. K., Li, Q. Z. & Miyazaki, T. Obesity-associated autoantibody production requires AIM to retain IgM immune complex on follicular dendritic cells. Cell Rep. 3: 1187-1198 (2013).
  11. Nakashima, K., Arai, S., Suzuki, A., Nariai, Y., Urano, T., Nakayama, M., Ohara, O., Yamamura, K-I., Yamamoto, K. & Miyazaki, T. PADI4 regulates proliferation of hematopoietic stem/multipotent cells via controlling c-Myc expression. Commun. 4: 1836 (2013).
  12. Gonzalez, N., Guillén, J. A., Gallardo, G., Diaz, M., de la Rosa, J. V., Casanova-Acebes, M., Hong, C., Lopez, F., Andujar, M., Lara, P. C., Arai, S., Miyazaki, T., Li, S., Tontonoz, P., Hidalgo, A. & Castrillo, A. The Nuclear Receptor LXRα controls the functional specialization of splenic macrophages. Immunol. 14: 831-839 (2013).
  13. Kurokawa, J., Nagano, H, Ohara, O., Kubota, N., Kadowaki, T., Arai, S., & Miyazaki, T. AIM is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue. Natl. Acad. Sci. USA. 108: 12072-12077 (2011).
  14. Kurokawa, J., Arai, S., Nakashima, K., Nishijima, A., Miyake, K., Ose, R., Mori, M., Kubota, N., Kadowaki, T., Oike, Y., Koga, H., Febbraio, M., Iwanaga, T. & Miyazaki, T. AIM is endocytosed into adipocytes and decreases lipid droplets via inhibition of fatty acid synthase activity. Cell Metab. 11: 479-492 (2010).
  15. Arai, S., Shelton, J.M., Chen, M., Bradley, M.N., Castrillo, A, Bookout, A.L., Mak, P.A., Edwards. P.A., Mangelsdorf, D.J., Tontonoz, P. & Miyazaki, T. A role of the apoptosis inhibitory factor AIM/Spalpha/Api6 in atherosclerosis development. Cell Metab. 1: 201-213 (2005).
  16. Miyazaki, T., Hirokami, Y., Matsuhashi, N., Takatsuka, H. & Naito, M. Increased susceptibility of thymocytes to apoptosis in mice lacking AIM, a novel murine macrophage-derived soluble factor belonging to the scavenger receptor cysteine-rich domain superfamily. J. Exp. Med. 189:413-422 (1999).

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