| Co-Investigator(Kenkyū-buntansha) |
HIRASAWA Akira Kyoto University, Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (70242633)
KOSHIMIZU Takaaki Kyoto University, Pharmaceutical Sciences, Assistant Professor, 薬学研究科, 講師 (20392491)
OKUNO Yasushi Kyoto University, Pharmaceutical Sciences, Associate Professor, 薬学研究科, 助教授 (20283666)
ADACHI Tetsuya Kyoto University, Pharmaceutical Sciences, Instructor, 薬学研究科, 研究員(COE) (60345014)
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| Research Abstract |
The result achieved for this research is summarized as following. The following research items planned at first were performed.
(1)Cloning of free fatty acid receptor family
(1)We cloned orphan G protein-coupled receptor GPR120 from genome database, and successfully de-orphanized ; hence, the natural ligand of GPR120 was free fatty acid. In this research, we performed cloning of all the other free fatty acid receptors (GPR40,GPR41,GPR43) by fully taking advantage of the genome database (human, mouse, and rat).
(2)Development of tools for in vivo/in vitro functional analysis
We succeeded in making specific antibodies agains to each free fatty acid receptor. Moreover, detailed information of tissue distribution of each receptor was collected. In addition, various compounds were screened by using a HTS signal transduction analysis platform, and found natural products specific to each receptor was found. Furthermore, we cloned mouse genomes of each receptor, and clarified the structure, and tr
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ied to generate genetically engineered animals (especially, knockout mouse), and eventually for part of the receptor family, we succeeded in generating knockout mouse.
(3)GPR120 function analysis
The in vitro function was analyzed by using native cell line STC-1 cell which are expressing GPR120, and we clarified that GPR120 plays a key role in regulating the secretion of incretin hormone GLP-1, which is important factor for insulin secretion. Moreover, we clarified that the GPR120-mediated secretion of GLP-1 is via the calcium and ERK signaling mechanism. Also, this GPR120 receptor-mediated signal transduction suppresses the apoptosis in this enteroendocrine cells.
Summary
We successfully prepared a various tools (e.g., specific antibodies, chemical probes, and knockout mice, etc.) to further analyze the physiological roles of free fatty acid receptor family. Based on this preparations, the physiological and pathophysiological role of these free fatty acid receptor family will be further clarified, and novel drug discovery can be expected in the future. Less
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