c-Met/HGFレセプターを介した傷害認識-再生駆動システムの解析

c-Met/HGF受体介导的损伤识别-再生驱动系统分析

• 批准号: 13045025
• 负责人: 松本 邦夫
• 金额: $ 1.47万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13045025/
• 关键词: HGF; c-Met; トランスジェニックマウス; チロシンキナーゼ; ノックアウトマウス; 再生・修復; 細胞増殖因子; 肝再生

傷害の察知と連携するc-Met/HGFレセプターのunfunctional(無傷)⇔functional(傷害)の機能変換機構の解明は、傷害組織特異的な再生駆動ならびに停止機構の解明につながるものと考えられる。本研究はc-Metレセプターの負の制御域(juxtamembrane領域)の欠失や領域内アミノ酸変異を導入したc-Metレセプター発現細胞を用いて、c-Metレセプター機能のON⇔OFF変換機構を生化学的に解明するとともに、傷害察知を介したc-MetレセプターのON⇔OFF変換の意義を遺伝子改変動物を用いて解明することを目的としている。1.c-Metレセプターのjuxtamembraneドメインを介した機能制御:c-Met/HGFレセプターのjuxtamembrane領域がc-MetのON⇔OFF機能変換に関与するものと推察した。そこで、1)リン酸化されたSer1002を認識する特異抗体の作成、2)Ser1002をAlaなどに置換したものやjuxtamembraneを欠質したc-Metを発現する細胞の樹立、3)HGF刺激による変異c-Metの活性化制御などの研究を行った。その結果、通常のc-MetはHGF刺激により急速な分解、一過的なチロシンリン酸化が引き起こされるのに対して、juxtamembraneを欠くc-MetではHGF刺激による分解が認められず、c-Metの活性化が長期に及ぶことが明らかとなり、これら結果から、juxtamembrane領域がc-Metの負の調節機能に関与する領域であることが示唆された。2.遺伝子改変動物を用いたc-MetのON⇔OFF機能変換の生理的意義の解析:Juxtamembraneを欠くc-Metを組織特異的に発現するノックインマウスを用いてON⇔OFF機能変換の生理的意義を明らかにする目的で、juxtamembrane領域をコードするexon14を欠質したc-Met遺伝子を相同組み換えにより導入されたES細胞を得た。現在、ノックインマウスの作成を急いでいる。

Injury detection and linkage c-Met/HGF detection mechanism unfunctional(non-injury) functional(injury) mechanism interpretation, injury tissue-specific regeneration mechanism interpretation and stop mechanism interpretation. In this study, the c-Met gene was introduced into the negative control domain (juxtamembrane domain), and the c-Met gene was used to develop cells. The on-off switching mechanism of c-Met gene function was used to explain the biological mechanism, injury detection mechanism, and the significance of on-off switching of c-Met gene. 1. The function control of the juxtamembrane of c-Met:c-Met/HGF: c-Met ON/OFF function control of c-Met. 1) Preparation of specific antibodies against Ser1002, 2) Establishment of cells with poor quality and c-Met production by Ser1002, 3) Study of activation of c-Met by HGF stimulation. As a result, c-Met is usually rapidly decomposed by HGF stimulation, and the decomposition of c-Met is recognized by HGF stimulation. The activation of c-Met is long-term, and the results are different. The negative regulatory function of c-Met is related to the domain of juxtamembrane. 2. Analysis of physiological significance of c-Met on/OFF function change in animal use:Juxtamembrane on/off function change in tissue-specific development of c-Met on/off function change in physiological significance of Juxtamembrane on/off function change in tissue specific development of c-Met on/off function change in tissue specific development of ES cells on/OFF function change in tissue specific development of c-Met on/off function change in tissue specific development of c-Met on/off function change in tissue specific development of ES cells on/off function change in tissue specific development of c-Met on/off function change in tissue specific development of ES cells on/off function change in tissue specific development of ES cells on/off function change in tissue specific development of c-Met on/off function change in tissue specific development of ES cells on/off function change in tissue specific development of c-Met on/off function change in tissue specific development of ES cells on/off function change in tissue specific development of c-Met on/off function change in tissue specific development of ES cells on/off function change in tissue specific development of c-Met on/off function change in tissue specific development of Now, you can make it happen.

项目成果

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