| Project/Area Number |
09044352
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Field |
General medical chemistry
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| Research Institution | Osaka Bioscience Institute |
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Principal Investigator |
URADE Yoshihiro Osaka Bioscience Institute, 2nd Dept., Vice-Head, 第2研究部, 副部長 (10201360)
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| Co-Investigator(Kenkyū-buntansha) |
AUSTEN K.Frank Harvard Medical School, the Department of Medicine, Professor, 医学部, 教授
HAYASHI Osamu Osaka Bioscience Institute, Director, 2nd Dept., Head, 所長, 部長 (40025507)
KUBATA B.Kilunga Osaka Bioscience Institute, 2nd Dept., Researcher, 研究員 (30291032)
GERASHCHENKO Dmitry JSPS,Postdoctoral Fellow, 外国人特別研究員 (90281609)
KANAOKA Yoshihide Osaka Bioscience Institute, 2nd Dept., Researcher, 研究員 (40271514)
FRANK Austen ハーバード大学, 医学部, 教授
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| Project Period (FY) |
1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 1997: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | Prostaglandin D2 / Prostaglandin synthase / beta-trace / Transporter / Evolution / X-ray crystallography / Knockout mice / Transgenic mice |
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| Research Abstract |
Prostaglandin (PG) D2 is a major prostanoid produced in the central nervous system of rats and humans, and is involved in a variety of central actions, i.e., it induces sleep and hypothermia and regulates odor and pain responses. PGD2 is also actively synthesized in mast cells and acts as an allergic and inflammatory mediator. There are two distinct types of PGD synthase, i.e., the lipocalin-type enzyme localized in the central nervous system, retina, and male genital organs and the hematopoietic enzyme distributed in the peripheral tissues. We demonstrated that the lipocalin-type enzyme is secreted as beta-trace into the cerebrospinal fluid, interphotoreceptor matrix, and seminal plasma and binds small liposhilic substances, such as retinoids, thyroids and bile pigments. Therefore, the lipocalin-type PGD synthase is considered to be a bifunctional protein which act as a PGD2-producing enzyme and also functions as a transporter protein for hydrophobic bioactive substances in those body fluids. The cDNA cloning of hematopoietic PGD synthase revealed that the amino acid sequence did not possess any significant homology with that of the lipocalin-type enzyme, indicating that these two enzymes have evolved from the unique ancestors distinct from one another. The lipocalin-type PGD synthase is a member of the lipocalin gene family, while the hematopoietic PGD synthase is the first recognized vertebtate homolog of the sigma class of glutathione S-transferase. We produced the recombinant lipocalin-type and hematopoietic enzymes, crystallized these enzymes, and determined the tartiary structure of the hematopoietic enzyme by X-ray crystallographic analysis. We also generated transgenic mice which overproduced each of those human enzymes and knockout mice lacking the gene for the lipocalin-type enzyme. We then examined the functional abnormality of the control nervous system, reproductive system, and immune responses of these mutant mice.
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