| Project/Area Number |
18390229
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
KURIHARA Hiroki The University of Tokyo, Graduate School of Medicine, Professor (20221947)
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| Co-Investigator(Kenkyū-buntansha) |
KURIHARA Yukiko The University of Tokyo, Graduate School of Medicine, Assistant Professor (80345040)
天野 朋和 東京大学, 大学院医学系研究科, 寄付講座教員(助手相当) (50359634)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥17,750,000 (Direct Cost: ¥15,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2007: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000)
Fiscal Year 2006: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | Endothelin / Craniofacial development / Cardiac development / Angiogenesis / G-protein coupling Receptor / Gene-manipulated mice / 心大血管 / 循環器疾患 / 個体発生 |
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| Research Abstract |
We have achieved the following results in regard to the molecular mechanisms underlying the involvement of the endothelin (ET) system in cardiovascular and craniofacial development and pathophysiology.
1. We have established the Cre-recombinase-mediated gene knock-in system in mouse ES cells, in which we can systematically replace the ET-A receptor (STAR) gene with exogenous genes.
2. By using this system, we knocked-in cDNAs encoding the ET-B receptor (ETBR) and ETAR-ETBR chimeric receptors. These experiments have revealed that i) both STAR subtype-selective and nonselective signaling are involved in the craniofacial development and ii) the induction of Dlx5/Dlx6 homeobox genes and subsequent specification of the mandibular identity is mediated by the STAR subtype-selective, Gq/G11-mediated signaling pathway.
3. Knock-in of the lacZ gene revealed a possible novel cell lineage originating within the cardiac crescent and contributing to the early cardiovascular development.
4. Knock-in of EGFP enabled us to visualize the STAR-positive cells in situ in mice, which is useful for the analysis of the dynamics of STAR-positive cells (e.g. smooth muscle cells) in embryonic vascular formation and in the physiological and pathophysiological processes.
5. We have identified Calpain-6 as a target molecule of the ET-1/STAR signaling pathway in craniofacial development. We have discovered the novel function of Calpain-6 in the stabilization of microtubules and actin organization involved in cellular morphology and motility. The studies on the developmental role of Calpain-6 are starting with its knockout mice established recently.
These achievements contribute to the understanding of the mechanisms of the cardiovascular and craniofacial development and pave a way to the development of experimental systems applicable to the studies on (patho)physiology involving the ET system.
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