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Application of TET2 as target in treatment of ischemic vascular diseases

A TET2, vascular disease technology, applied in the field of biomedicine, can solve the problem of lack of research revealing the regulation effect, achieve good clinical application prospects, improve blood flow recovery, and achieve the effect of precise treatment

Pending Publication Date: 2022-04-29
ZHONGSHAN HOSPITAL FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, no studies have revealed whether TET2 in endothelial cells plays a regulatory role in angiogenesis in ischemic vascular diseases and its specific mechanism

Method used

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  • Application of TET2 as target in treatment of ischemic vascular diseases
  • Application of TET2 as target in treatment of ischemic vascular diseases
  • Application of TET2 as target in treatment of ischemic vascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1 Correlation between hypoxia and TET2 in endothelial cells

[0027] In order to verify whether hypoxia affects the expression level of TET2 in endothelial cells, the transcription and expression levels of TET2 in human umbilical vein endothelial cells (HUVEC) were detected by RT-qPCR method and Western blot respectively under hypoxia treatment at different times. The results are as follows: figure 1 , 2 As shown, the transcriptional and protein expression levels of TET2 were time-dependently down-regulated with hypoxia.

Embodiment 2

[0028] Example 2 Inhibition of TET2 Enhances Tube Formation and Invasion Ability of Endothelial Cells

[0029] (1) Knockout of TET2 in HUVEC cells:

[0030] In order to further investigate whether TET2 is involved in the regulation of angiogenesis, at the cellular level, this example used Lipofectamine 3000 (Invitrogen) in HUVEC cells, and according to the instructions, transfected siScramble (NC group, negative control group), siTET2 (in the experiment Three pairs of interference sequences were used for the experiment, namely: siTET2-1 / siRNA-1: ACAAGAAAGUAGAGGGUAUTT, siTET2-2 / siRNA-2: GGGUAAGCCAAGAAAGAATT, siTET2-3 / siRNA-3: AGAAAGAAAUCCAGGUGAATT), after 24 hours of transfection, respectively, by RT-qPCR and Western blotting were used to detect the transcriptional and protein expression levels of TET2 in human umbilical vein endothelial cells (HUVEC), as shown in image 3 , 4 As shown, the results indicated that TET2 was successfully knocked out.

[0031] (2) Matrigel tube-...

Embodiment 3

[0035] Example 3 Knockout of TET2 in mouse endothelial cells accelerates blood flow recovery in ischemic tissues

[0036] (1) Construction of endothelial cell TET2 conditional knockout mice

[0037]Through CRE-Floxp technology, TET2-Flox mice were constructed and crossed with CDH5-ERT2-Cre mice to successfully obtain endothelial cell TET2-specific conditional knockout mice.

[0038] (2) Construction of lower extremity ischemia model

[0039] All experimental mice WT and TET2KO mice were skinned one day before femoral artery ligation, and the abdomen and lower limbs were depilated with depilatory cream. Pentobarbital sodium 8mg / mL was anesthetized by intraperitoneal injection of 10mL / kg. The mice were placed in a supine position, their lower limbs were fixed with adhesive tape, and the surgical field of view of the right lower limb was exposed. Cut a longitudinal incision of 2.5-3 cm along the direction of the blood vessels, and carefully bluntly dissect the blood vessels an...

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Abstract

The invention discloses application of TET2 as a target in treatment of ischemic vascular diseases. According to the application disclosed by the invention, the effect of TET2 in endothelial cell tubulation and invasion is verified through tubulation and Transwell experiments at the cellular level. According to the application, the effect of TET2 in blood flow recovery is verified by using an endothelial cell specific TET2 knockout mouse at an animal level, and blood flow recovery in a lower limb ischemia model can be remarkably improved by knocking out TET2 through tissue specificity. A new treatment target spot is found for clinically treating the ischemic vascular disease, especially the peripheral artery disease, the endothelial cell deletion TET2 is targeted, and precise treatment of the ischemic vascular disease, especially the peripheral artery disease, is expected to be achieved.

Description

technical field [0001] The invention relates to the application of TET2 as a target in the treatment of ischemic vascular diseases, and belongs to the technical field of biomedicine. Background technique [0002] Angiogenesis is critical for tissue regeneration or repair in conditions such as wound healing, muscle and bone repair, hypoxia and chronic ischemia. Limb ischemia is one of the most common forms of peripheral arterial disease and is associated with cardiovascular events including stroke and myocardial infarction. In the late 1990s, humans first tried to use gene therapy to treat severe limb ischemic diseases. So far, there are few therapeutic options other than endovascular therapy to restore blood flow to ischemic tissue. Therefore, finding key regulators of angiogenesis as therapeutic targets is of great significance for promoting blood flow restoration in vivo. [0003] TET (Ten-eleven translocation) protein is a newly discovered class of DNA demethylases, wh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/7088A61P9/10
CPCA61K45/00A61K31/7088A61P9/10
Inventor 孙爱军葛均波洪文轩
Owner ZHONGSHAN HOSPITAL FUDAN UNIV
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