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[Hokkaido University]
Nagara Tamaki, Hirotoshi Akita, Yuji Kuge, Chietsugu Kato, Kikuo Umegaki, Sato Honma, Zhao Songji,
Komei Washino, Tohru Shiga, Toshiyuki Hamada, Ken-ichi Nishijima, Ryosuke Enoki, Yoichi Shimizu,
Feng Fei, Yoshihiro Hirata, Daisuke Ono, Tomoko Yoshikawa, Eriko Suzuki, (Keiichiro Yoshinaga)

[Hitachi, Ltd.]
Keiji Kobashi, Hisaaki Ochi, Takeshi Sakamoto, Kenichi Kawabata, Norihito Kuno, Hiroko Hanzawa,
Atsurou Suzuki, Wataru Takeuchi, Kazuki Matsuzaki, Naomi Manri

[Nihon Medi-Physics Co., Ltd.]
Yoshifumi Shirakami, Hiroki Matsumoto, Norihito Nakata, Masato Kiriu

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To establish methods for predicting the onset of illnesses and for super-early diagnosis that will be used in the patient-tailored medical care of the future, this hub aims at establishing a molecular catalog (library) of all available information on bio-molecules. We will achieve molecular multimodal imaging by integrating optical imaging with other imaging modalities (PET, MRI). Using the developed method, we will create an atlas of molecular images in the molecular library. To accomplish these purposes, we are focusing on 1) Development and clinical application of radio-labeled molecular probes, 2) Research and development of long-term and real-time molecular photonic-bioimaging, 3) Application of integrated imaging to experimental animals and humans.

1) Development and clinical application of radio-labeled molecular probes
Using appropriate radio-labeled molecular probes, we develop imaging techniques that enable quantitative determination of biological functions at cellular/molecular levels, such as hypoxic environment in tumors, receptor functions/signal transductions of the sympathetic nervous system, molecular mechanism of atherosclerosis, and functional changes induced by radiation and molecular targeted therapies.
We have investigated radio-labeled molecular probes that visualize the pathological changes in tumors, heart failure, and cerebral ischemia. Based on the investigations, we have successfully achieved clinical application of a radio-labeled molecular probe for imaging hypoxic cells (18F-FMISO). Clinical studies using 18F-FMISO are in progress and new hypoxia probes with improved pharmacokinetic characteristics are now in development collaborating with Nihon Medi-Physics Co., Ltd, In addition, clinical application of C-11 labeled hydroxyephedrine, a molecular probe for pre-synaptic functions, has been achieved and clinical studies to establish diagnostic imaging of sympathetic nervous system are ongoing in patients with heart failure. Moreover, we have started basic studies on molecular mechanisms of atherosclerosis collaborating with Hitachi Ltd..
Our next challenge is to establish diagnostic strategies of tumors, heart failure based on the hypoxia and sympathetic nerve imaging, utilizing radio-labeled molecular probes. In addition, we intend to develop imaging probes/techniques that enable quantitative determination of cellular/molecular changes induced by radiation and molecular targeted therapies and observed in unstable atherosclerotic plaques.


Development of radio-labeled molecular probes for imaging biological functions at cellular/molecular levels

2) Research and development of long-term and real-time molecular photonic-bioimaging

Using highly sensitive bioluminescent probes, we improve in vivo and ex vivo real-time molecular imaging systems and develop the techniques of long-term monitoring, which enable us to analyze molecular functions at the level of cells, tissues and even of living animals in various disease models such as transgenic, mutant and tumor-bearing animals and differentiation models.
In order to know the functional roles of the molecules of interest in the pathogenesis and progress of diseases, we have introduced spatiotemporal analyses of photonic bioimaging in culture system and free-moving animals. By applying in vivo micro-optic fiber imaging system to the transgenic mice carrying a luciferase reporter gene, we now can monitor the targeted molecules in specific region or organs in free-moving animals (A,B). We also develop a novel imaging system to follow the targeted molecules in the tissues at high spatio-temporal resolution (C-E). Furthermore, in order to elucidate the biological functions of clock genes during chondrogenic differentiation, we constructed a dual-path luminescence imaging system for the simultaneous monitoring of the expression of two genes from single-cells using a dual-color reporter system (F). The dual-color bioluminescence imaging showed the anti-phasic expression of Bmal1 and Per2, two canonical clock genes, with a circadian period of ~24 h in individual cells (G). We introduce these bioluminescence reporting systems to long-term monitoring of "cancer circadian rhythm" in order to establish ideal chronotherapy model system.
By extending these experiments and imaging techniques, we will examine the development and recovery processes of diseases so that we could dramatically improve the evaluations of the stages of disorders and therapeutic effects of treatments, which in turn, may accelerate pre-clinical research. Therefore, by incorporating new techniques such as multi-color probes, micro-optic fibers and multi-photon deep-tissue imaging system into the real-time monitoring, we will monitor the functional molecules in free-moving animals at high spatio-temporal resolution.


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3) Application of integrated imaging to experimental animals and humans

Taking advantage of novel probes for bioluminescent- and radio-labeled imaging probes developed in this program, we intend to evolve the in vivo imaging of molecules of interest in experimental animals and humans. Visualization and spatiotemporal analyses of functional molecules in response to various treatments will markedly improve our understanding of the pathogenesis of diseases, leading to personalized medicine.
In this program, we have already established basic techniques for photonic bioimaging, including molecular dynamic imaging, imaging using new radio-labeled probes and long-term and real-time molecular imaging using bioluminescent probes. Taking all these achievements together, we are now constructing an integrated imaging system for experimental animals. Imaging studies are performed with a highly sensitive cooled CCD camera for the bioluminescent probes, and PET scanners and semiconductor detectors developed by collaboration with Hitachi, Ltd. for the radio-labeled probes. In bioluminescence studies by means of reporter enzyme firefly luciferase (luc) and substrate luciferin, we developed In vivo 4D imaging system for long time recording of the gene expression in freely moving mouse using real-time luminescence-tracking technique(In vivo 4D imaging). Clinical studies are in progress using PET scanners and RI probes to evaluate their potentials for therapy planning, and efficacy and prognosis assessment of medical treatments. Furthermore, utilizing these techniques and collaborating with drug discovery group, we are now conducting researches 1) to determine the best target molecules for medical treatment through the accurate assessment of functional abnormalities in receptors and/or signal transductions, 2) to design the best treatment plan and monitoring system of cancer and atherosclerosis through the visualization of functional abnormalities at cellular/molecular levels including apoptotic changes, and 3) to establish monitoring system for gene expression, functional changes and therapy response in gene therapy and regeneration medicine.


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Coordinating Office, Future Drug Discovery and Medical Care Innovation Project
Kita 21, Nishi 10, Kita-ku, Sapporo, Hokkaido 001-0021, Japan
Tel: +81-(0)11-706-9188 Fax: +81-(0)11-706-9190

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