VEGFR2 Trafficking by KIF13B Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration.
VEGFR2 Trafficking by KIF13B Is a Novel Therapeutic Target for Wet Age-Related Macular Degeneration.
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KIF13B的VEGFR2运输是与湿年龄相关的黄斑变性的新型治疗靶标。
DOI：
10.1167/iovs.62.2.5
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发表时间：
2021-02-01
影响因子：
4.4
通讯作者：
Yamada KH
中科院分区：
文献类型：
--
作者：
Waters SB;Zhou C;Nguyen T;Zelkha R;Lee H;Kazlauskas A;Rosenblatt MI;Malik AB;Yamada KH
血管内皮生长因子（VEGF）及其受体VEGFR2是治疗湿性年龄相关性黄斑变性（AMD）的有希望的靶点。作为局部适用的选择，我们开发了肽KAI来选择性地干扰VEGFR2运输到细胞表面，在那里它接受VEGF。本研究旨在确定KAI对小鼠脉络膜新生血管（CNV）模型的疗效。通过表面等离子体共振检测KAI的特异性。采用冷冻切片和酶联免疫吸附法分析KAI滴眼液给药小鼠眼后的给药情况。对于激光诱导的CNV模型，激光诱导的Bruch膜破裂小鼠每天给予KAI滴眼液或对照肽治疗。其余各组小鼠玻璃体内注射抗vegf或IgG对照。两周后，对CNV进行量化比较。首先，我们展示了KAI对VEGFR2的特异性和高亲和力。接下来，生物分布显示KAI滴眼液成功递送到小鼠眼后。KAI显著降低了激光诱导CNV的疾病进展。与目前治疗方法的比较表明，KAI滴眼液与目前治疗方法一样有效预防湿性AMD的CNV。此外，介导VEGFR2转运到细胞表面的激酶蛋白KIF13B的基因缺失证实了KIF13B在湿性AMD的疾病进展和脉络膜血管新生血管中的关键作用。综上所述，药物抑制和基因缺失相辅相成，表明靶向VEGFR2转运抑制湿性AMD病理性血管生成的治疗可能性。
Vascular endothelial growth factor (VEGF) and its receptor VEGFR2 are promising therapeutic targets for wet age-related macular degeneration (AMD). As a topically applicable option, we developed the peptide KAI to selectively interfere with VEGFR2 trafficking to the cell surface where it receives VEGF. This study sought to determine the efficacy of KAI in the mouse model of choroidal neovascularization (CNV). The specificity of KAI was tested by surface plasmon resonance. The drug delivery was analyzed by cryosection and the ELISA after treatment of KAI eyedrop to the mouse eyes. For the laser-induced CNV model, mice with laser-induced ruptures in Bruch's membrane received daily treatment of KAI eyedrop or control peptide. The other groups of mice received intravitreal injection of anti-VEGF or IgG control. After two weeks, CNV was quantified and compared. First, we showed the specificity and high affinity of KAI to VEGFR2. Next, biodistribution revealed successful delivery of KAI eyedrop to the back of the mouse eyes. KAI significantly reduced the disease progression in laser-induced CNV. The comparison with current therapy suggests that KAI eyedrop is as effective as current therapy to prevent CNV in wet AMD. Moreover, the genetic deletion of a kinesin KIF13B, which mediates VEGFR2 trafficking to the cell surface, confirmed the pivotal role of KIF13B in disease progression of wet AMD and neovascularization from choroidal vessels. Taken together, pharmacologic inhibition and genetic deletion complementarily suggest the therapeutic possibility of targeting VEGFR2 trafficking to inhibit pathological angiogenesis in wet AMD.
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血管内皮钙粘蛋白控制着细胞内室的VEGFR-2内在化和信号传导。
影响因子：
7.8
作者：
Lampugnani, Maria Grazia;Orsenigo, Fabrizio;Gagliani, Maria Cristina;Tacchetti, Carlo;Dejana, Elisabetta
通讯作者：
Dejana, Elisabetta
影响因子：
11.8
作者：
Lanahan, Anthony A.;Hermans, Karlien;Claes, Filip;Kerley-Hamilton, Joanna S.;Zhuang, Zhen W.;Giordano, Frank J.;Carmeliet, Peter;Simons, Michael
通讯作者：
Simons, Michael
DOI：
10.1083/jcb.201205070
发表时间：
2012-08-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jenkins B;Decker H;Bentley M;Luisi J;Banker G
通讯作者：
Banker G
影响因子：
3.9
作者：
Ehlken, C.;Jungmann, S.;Pielen, A.
通讯作者：
Pielen, A.
影响因子：
4.2
作者：
Krohne, Tim U.;Liu, Zengping;Meyer, Carsten H.
通讯作者：
Meyer, Carsten H.