Yuji Kuge, Zhao Songji, Komei Washino, Ken-ichi Nishijima, Yoichi Shimizu, Feng Fei, (Keiichiro Yoshinaga)
Yasuro Shinohara, Junichi Furukawa, Masumi Tsuda
Kiyohiro Houkin, Norihiro Sato, Hiroshi Takeda, Naoya Sakamoto, Nobuhisa Ishiguro,
Hideaki Miyoshi, Shunsuke Onishi, Koji Ogawa, Hideo Shichinohe, (Satoshi Kuroda)
[Shionogi & Co., Ltd.]
Takeshi Shiota, Yoshinori Yamano, Masashi Deguchi, Yoshito Numata, Kenichi Higashino, Yutaka Yoshida,
Hiroshi Takemoto, Hideo Yukioka, Yoshitaka Yamaguchi
Takeshi Sakamoto, Norihito Kuno, Hiroko Hanzawa, Naomi Manri
[Nihon Medi-Physics Co., Ltd.]
Yoshifumi Shirakami, Hiroki Matsumoto, Norihito Nakata, Masato Kiriu
Placing priority on patient QOL, we aim at standardizing methods for the fast, focused discovery of drugs by integrating next-generation, biologics drug discovery with individualized, optical-metrological-based medical care. The drug discovery and medical care groups will closely collaborate to conduct the clinical trials that are required for determining the reliability of lipid and glycan-based biomarkers for diagnosis, and researches on imaging techniques for realizing screening of pharmacokinetics and efficacy of drug candidate compounds developed by our drug discovery group.
To achieve our goals, we have been researching the use of optical/RI imaging as a part of our drug discovery and translational research.
1) Research on the use of optical/RI imaging in drug discovery and translational research
In conventional drug discovery research, small animals are used in great numbers for preclinical tests. It is very possible that in the near future, in vivo quantitative kinetic studies on small animals will use photon bio-imaging and RI imaging, such as PET, in place of the current method. The drug discovery network and medical care network of Hokkaido University will link themselves together via the Photon-positron Research Hub and conduct research that greatly shortens the drug discovery process.
The medical care group and Hitachi, Ltd. has developed a semiconductor-equipped imaging device for small animals and has successfully determined the in vivo kinetics of the radioiodine marker synthesized using as therapeutic candidate (sugar-chain modified glucagon-like peptide (GLP-1)) found by the drug discovery group. In addition, medical care group, collaborating with Shionogi & Co. Ltd., confirmed the usefulness of apoptosis imaging in the evaluation of diabetes mellitus and atherosclerosis in animal models. Potentials of RI imaging for the assessment of molecular-targeted therapies and cell therapies have been also suggested. The experiments have revealed that the imaging devices developed by Hitachi, Ltd. are effective for drug discovery, thanks to the performance of the semiconductors.
Paying attention to the NIH and FDA, we will continue our R&D on a high-resolution PET for small animals with higher performance than those of the present international standards.
In collaboration with the project hub for next-generation post-genomic drug discovery, we will establish new marker technologies for analyzing, in vivo, the dynamics of promising compounds, biomarker candidates and disease-related proteins that are being developed under the project. We will develop optical/RI imaging technologies and apply them to equipment installed with semiconductors. These new developments will greatly shorten the drug discovery process.
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2) Biomarker discovery based on the total glycomics in close cooperation with medical front
Although glycoconjugates has shown great promise as sources of biomarkers, they had never been systematically explored due to the technical limitations. As one of the outcomes of the project, a concept and methodology of total cellular glycome, a systematic overview of major classes of cellular glycome, has been proposed and established. A panoramic view of the total glycome allows a priori identification of known pluripotency biomarkers as well as a panel of glycans specifically expressed by human stem cells. A unique approach for the discovery of novel biomarkers based on the total cellular glycomics using highly quality controlled clinical samples is currently in progress, especially in the fields of brain tumor pathology and central nervous system regenerative medicine.
drug discovery based on clinical demands
The purpose of the current project is to elucidate the pathogenesis of retinal diseases driven by the renin-angiotensin system (RAS) and establish novel medical treatment. We have shown that (pro)renin receptor [(P)RR] plays a key role in the tissue RAS activation in retinal disorders including diabetic retinopathy (DR) and age-related macular degeneration. Recently, we elucidated (P)RR-associated pathogenesis of fibrovascular proliferation in human DR. (P)RR immunoreactivity was detected in vascular endothelial cells in surgically excised fiborovascular tissues. Protein levels of soluble (P)RR in the vitreous fluids from patients were higher in proliferative DR eyes than in non-diabetic control eyes, and were significantly correlated with vitreous levels of vascular endothelial growth factor (VEGF) and the vascular density of fibrovascular tissues. Our data using human samples provide the first evidence that (P)RR is associated with angiogenic activity in PDR. We aim to establish optimized treatment specifically for pathologic conditions while investigating unknown functions of (P)RR including physiologic roles.