| Project/Area Number |
10671477
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Urology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
MURAKAMI Takashi The Tokushima University, School of Medicine, Instructor, 医学部, 助手 (40210009)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAMOTO Tadayuki The Tokushima University, Medicine School Hospital, Associate Professor, 医学部・附属病院, 講師
ISHIMURA Kazunori The Tokushima University, School of Medicine, Professor, 医学部, 教授 (90112185)
KUWAJIMA Masamichi The Tokushima University, School of Medicine, Associate Professor, 医学部, 助教授 (00205262)
TANAKA Toshihiro University of Tokyo, Human Genome Center, Instructor, 医科学研究所・ヒトゲノム解析センター, 助手 (50292850)
TOSHIMORI Kiyotaka Miyazaki Medical College, Professor, 医学部, 教授 (20094097)
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1999: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1998: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | carnitine / carintine transporter / infertility / JVS mouse / octn2 / epidiymis / THP / azoospermia / 精巣上体 / 全身性カルニチン欠乏マウス / 閉塞性無精子症 |
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| Research Abstract |
Juvenile Visceral Steatosis (JVS) mouse, which we reported in 1991, serves as an animal model of primary carnitine deficiency. Because this mouse is suffered from severe male infertility, we analyzed the cause and mechanism. The summary of the results is as follows ;
1. Analysis of candidate gene
As a human OCTN2 gene encoding a sodium-dependent carnitine cotranspoter was isolated, we isolated the mouse octn2 gene and screened for its mutation in the JVS mouse. DNA sequencing analysis disclosed a missense mutation from CTG (Leu) to CGG (Arg) at codon 352 located within the sixth transmembrane domain of octn2. This amino acid replacement possibly causes the conformational change of the protein that leads to dysfunction of the gene product.
2. Analysis of epididymis
At 8-9 weeks of age, the epididymis was deformed, and its weight was significantly increased. Histologically, the duct of proximal epididymis was dilated due to the accumulation of unusually high level of spermatozoa. Spermatozoa ware extravasated from the epididymal duct into the stroma. In contrast, the duct of the distal epididymis was constricted and contained no spermatozoa. Thus, the epididymal disorder causes obstructive azoospermia, leading to infertility.
3. Discovery of camitine transport inhibitor
The site of action of 3-(2,2,2-trimethylhydrozinium) propionate (THP), a new cardioprotective agent, was investigated in mice and rats. As a result, it was indicated that the principal site of action of THP is the carnitine-transport carrier in kidney but not the carrier in heart.
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