Structure and function of VEGF receptors related to preeclampsia.

与先兆子痫相关的 VEGF 受体的结构和功能。

• 批准号: 17390110
• 负责人: SHIBUYA Masabumi
• 金额: $ 8.38万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390110/
• 关键词: angiogenesis; VEGF; VEGF receptor; renal dysfunction; VEGF受容体-1; 妊娠; 胎盤; trophoblast stem cells; RNAi

Preeclampsia is a major disease in gynecological field. Recent studies strongly suggest that soluble form of Flt-1 (sFlt-1/sVEGFR1) is deeply involved in this disease. We attempted to understand the whole functions of Flt-1 protein including sFlt-1.1, We found that trophoblast stem cell (TS cell) system could be a good model for flt-1 gene expression, since in placenta, trophoblast cells are the major producer for sFlt-1. During the differentiation, flt-1 mRNA was 5-fold elevated, suggesting a physiological gene expression. However, we could not find a stress which abnormally upregulate the expression of sflt-l. Such a stress could be a candidate for inducer of preeclampsia.2, We examined the effect of exogenous VEGF-A and sFlt-1 on pregnant mice. We found that exogenous VEGF-A induces pathological change at placenta such as fibrin deposition, and exogenous sFlt-1 transiently induces hypertension and proteinurea. However, to maintain these phenotypes, a large amount of sFlt-1 appears to be required.3, sFlt-1 protein efficiently blocked abnormally secreted VEGF-A from ascites tumors, resulting in suppression of ascites volume and tumor growth in ascites. Thus, sFlt-1 protein is a good candidate for an inhibitor of pathological VEGF-A and ascites tumor.4, Flt-1 signaling-deficient mice (Flt-1 TK-/- mice) showed a milder phenotype in arthritis-model, indicating that tyrosine kinase of Flt-1 is a new target for the treatment of rheumatoid arthritis.Dr.Ambati' s group collaborating with us found that sFlt-1 is an important natural molecule for maintaining avascularity in cornea.

子痫前期是妇科领域的一大疾病。最近的研究有力地表明，可溶性Flt-1(sFlt-1/sVEGFR1)与本病密切相关。我们试图了解包括sFlt-1.1在内的Flt-1蛋白的完整功能，我们发现滋养层干细胞(TS细胞)系统可能是Flt-1基因表达的一个很好的模型，因为在胎盘中，滋养层细胞是sFlt-1的主要产生细胞。在分化过程中，Flt-1mRNA表达水平升高5倍，提示可能是生理基因的表达。然而，我们没有找到一种异常上调sflt-L表达的应激。此应激可作为子痫前期的诱因。2.检测外源性VEGF-A和sFlt-1对妊娠小鼠的影响。我们发现外源性的血管内皮生长因子-A可引起胎盘的纤维蛋白沉积等病理改变，而外源性的sFlt-1可短暂地引起高血压和蛋白尿素。然而，要维持这些表型，似乎需要大量的sFlt-1。3、sFlt-1蛋白有效地阻断了腹水肿瘤异常分泌的VEGF-A，从而抑制了腹水体积和腹水中肿瘤的生长。4、Flt-1信号缺陷小鼠(Flt-1 TK-/-小鼠)在关节炎模型中表现出较温和的表型，表明Flt-1酪氨酸激酶是治疗类风湿关节炎的新靶点。Ambati博士的S博士与我们合作发现，sFlt-1是维持角膜血管紧张性的重要天然分子。

项目成果

Signaling of vascular endothelial growth factor receptor-1 tyrosine kinase promotes rheumatoid arthritis through activation of monocyte/macrophages.

血管内皮生长因子受体 1 酪氨酸激酶的信号传导通过单核细胞/巨噬细胞的激活促进类风湿性关节炎。

• 发表时间: 2006
• 期刊: Blood 108
• 作者: Murakami;M.;Iwai;S.;Hiratsuka;S.;Yamauchi;M.;Nakamura;K.;Iwakura;Y.;Shibuya;M
• 通讯作者: M

Vascular endothelial growth factor receptor-1 signaling is essential for osteoclast development and bone-marrow formation in CSF-1-deficient mice.

血管内皮生长因子受体 1 信号传导对于 CSF-1 缺陷小鼠的破骨细胞发育和骨髓形成至关重要。

• 发表时间: 2005
• 期刊: Proc. Natl. Acad. Sci. USA 102
• 作者: Niida;S.;Kondo;T.;Hiratsuka;S.;Hayashi;S. -I.;Amizuka;N.;Noda;T.;Ikeda;K.;Shibuya;M
• 通讯作者: M

Corneal avascularity is due to soluble VEGF receptor-1.

• DOI: 10.1038/nature05249
• 发表时间: 2006-10-26
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Ambati, Balamurali K.;Nozaki, Miho;Singh, Nirbhai;Takeda, Atsunobu;Jani, Pooja D.;Suthar, Tushar;Albuquerque, Romulo J. C.;Richter, Elizabeth;Sakurai, Eiji;Newcomb, Michael T.;Kleinman, Mark E.;Caldwell, Ruth B.;Lin, Qing;Ogura, Yuichiro;Orecchia, Angela;Samuelson, Don A.;Agnew, Dalen W.;St. Leger, Judy;Green, W. Richard;Mahasreshti, Parameshwar J.;Curiel, David T.;Kwan, Donna;Marsh, Helene;Ikeda, Sakae;Leiper, Lucy J.;Collinson, J. Martin;Bogdanovich, Sasha;Khurana, Tejvir S.;Shibuya, Masabumi;Baldwin, Megan E.;Ferrara, Napoleone;Gerber, Hans-Peter;De Falco, Sandro;Witta, Jassir;Baffi, Judit Z.;Raisler, Brian J.;Ambati, Jayakrishna
• 通讯作者: Ambati, Jayakrishna

VEGF-A is involved in guidance of VEGF-receptor-positive cells to the anterior portion of early embryos.

VEGF-A 参与将 VEGF 受体阳性细胞引导至早期胚胎的前部。

• 发表时间: 2005
• 期刊: Mol. Cell. Biol. 25
• 作者: Hiratsuka;S.;Kataoka;Y.;Nakao;K.;Nakamura;K.;Morikawa;S.;Tanaka;S.;Katsuki;M.;Maru;Y.;Shibuya;M
• 通讯作者: M

Locating inositol 1,4,5-trisphosphate in the nucleus and neuronal dendrites with genetically encoded fluorescent indicators.

使用基因编码的荧光指示剂在细胞核和神经元树突中定位肌醇 1,4,5-三磷酸。

• 发表时间: 2005
• 期刊: Anal Chem. 77
• 作者: Sato;M.;Ueda;Y.;Shibuya;M.;Umezawa;Y.
• 通讯作者: Y.