Application of adp receptor p2y12 in angiogenesis

A technology of p2y12 and angiogenesis, applied in the field of developmental biology and biomedicine, can solve the problem of unclear expression level of dll4 in cutting-edge cells

Active Publication Date: 2018-10-16
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Nonetheless, which signaling pathways control the expression levels of DLL4 in tip cells remains unclear

Method used

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  • Application of adp receptor p2y12 in angiogenesis
  • Application of adp receptor p2y12 in angiogenesis
  • Application of adp receptor p2y12 in angiogenesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] The highly conserved ADP receptor p2y12 is specifically expressed in zebrafish vascular endothelial cells

[0175] Purine signaling pathway is an important conserved signaling pathway, which is known to be involved in many biological processes, but whether it is involved in the process of vascular development in vivo is still poorly understood.

[0176] In this example, the inventors cloned the ADP receptor p2y12 in zebrafish, and found that it has a high degree of interspecies conservation after homology comparison. Compared the amino acid sequence of the zebrafish p2y12 protein with the homologous gene protein sequences of humans and mice, it was found that there were 45.326% (160) identical amino acids and 66.86% (230) similar amino acids, showing a very High conservatism ( figure 1 A); figure 1 B is the homology tree of p2y12 and its homologous genes in human and mouse.

[0177] Using the whole embryo in situ hybridization technique, the inventors further detecte...

Embodiment 2

[0179] Relationship between p2y12 and angiogenesis

[0180] In this example, the inventors designed an inhibitor against the sequence of the translation initiation region of zebrafish p2y12 mRNA: morpholino, namely p2y12MO (sequence shown in SEQ ID NO: 2), and knocked down the expression of p2y12 in zebrafish embryos with morpholino.

[0181] Firstly, the effectiveness of p2y12MO was verified: the p2y12MO binding sequence was placed at the 5' end of egfp to construct a reporter gene, and its in vitro transcription product was mixed with control MO or p2y12MO and injected, and red fluorescence was used as an internal reference.

[0182] As a result, it was observed that the embryo injected with the inhibitor p2y12MO had a green fluorescence expression significantly weaker than that of the embryo injected with p2y12MO, and the length of the ISV of the embryo injected with p2y12MO was shorter than that of the control in 30 hours after fertilization), confirming that the inventor's...

Embodiment 3

[0186] Activation of p2y12 by ADP is essential for angiogenesis

[0187]p2y12 is one of the receptors of ADP, the inventors use the highly selective antagonist MRS2395 (the antagonist binds to p2y12 competitively with ADP, see Developmental Cell 22,1-11, June 12,2012), to block The combination of ADP and p2y12, so as to detect whether the effect of p2y12 on blood vessel development comes from being activated by ADP. The drug MRS2395 was added to the embryo culture medium 12 hours after fertilization, with a final concentration of 10 ng / μl, and the control was adding a corresponding volume of solvent DMSO to the embryo culture medium at the same time point).

[0188] The results showed that the development of intersegmental blood vessels in embryos 24 hours after fertilization was normal, while the development of intersegmental blood vessels in embryos 30 hours after fertilization was obviously defective. Figure 5 A- Figure 5 B shows that, 24 hours after fertilization, the ...

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Abstract

The invention relates to an application of a receptor p2y12 of ADP (adenosine diphosphate) in angiogenesis. Concretely, the receptor p2y12 of ADP is specifically expressed in vascular endothelial cells, and a specific inhibitor of p2y12 is used for inhibiting p2y12 expression and preventing blood vessels among somites from generating growth defects; the ligand ADP of p2y12 is also involved in angiogenesis, and a high-selectivity antagonist is utilized to block ADP to activate p2y12 to have an exception which is the same as the above exception; an ADP-p2y12 signal is involved in the angiogenesis process in modes of migrating and proliferating tip cells, namely regulating tip cell behaviors; otherwise, p2y12 overexpression can promote the obtaining of tip cell, namely the number of endothelial cells with excessive migration and endothelial cells involved in angiogenesis among somites is obviously increased; in addition, the ADP-p2y12 signal inhibits a notch pathway so as to regulate angiogenesis in vivo. The application of the receptor p2y12 of ADPin angiogenesis provides a new target for related diseases of intervention in angiogenesis.

Description

technical field [0001] The invention belongs to the field of developmental biology and biomedicine, in particular, the application of ADP receptor p2y12 in angiogenesis. Background technique [0002] Angiogenesis refers to the process of forming new blood vessels through the proliferation and migration of vascular endothelial cells on the basis of the original capillary network. Angiogenesis plays an important role in physiological processes such as embryonic development and injury repair in vivo. It is also the main cause of many neovascular diseases, such as tumor growth and metastasis, proliferative diabetic retinopathy, retinopathy of prematurity, and rheumatoid arthritis. pathological changes. Therefore, the research and application of neovascularization inhibitors are of great significance for some refractory neovascularization-related diseases. [0003] In the process of angiogenesis, different vascular endothelial cells have different grades and also have different...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K39/395A61K38/00A61K48/00A61P35/00A61P9/00C12Q1/6886C12Q1/02
Inventor 荆清李文庆李方方谌健
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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