Met调控的变构神经再生模块作为治疗鼠脑缺血的新靶点

Kang-ning LI; Ying-ying ZHANG; Ya-nan YU; Hong-li WU; Zhong WANG

doi:10.1007/s11655-019-3182-8

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Met调控的变构神经再生模块作为治疗鼠脑缺血的新靶点

Original Article | Updated：2021-11-29

- Met调控的变构神经再生模块作为治疗鼠脑缺血的新靶点
- Met-Controlled Allosteric Module of Neural Generation as A New Therapeutic Target in Rodent Brain Ischemia^*
- Chinese Journal of Integrative Medicine 2021年27卷第12期页码：896-904
- Affiliations：
  
  1.Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing (100070), China
  2.Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing (100700), China
- Author bio：
  
  Prof. WANG Zhong, E-mail: zhonw@vip.sina.com
- Funds：
  
  Beijing Natural Science Foundation(7174298);Miaopu Project of Beijing Tiantan Hospital affiliated to Capital Medical University(2014MP04);the 51th lot General Financial Grant from the China Postdoctoral Science Foundation(2012M510723)
- DOI：10.1007/s11655-019-3182-8
  中图分类号：
- 纸质出版日期：2021-11-15，
  
  网络出版日期：2019-08-15，
  
  录用日期：2019-05-05
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Kang-ning LI, Ying-ying ZHANG, Ya-nan YU, 等. Met调控的变构神经再生模块作为治疗鼠脑缺血的新靶点[J]. Chinese Journal of Integrative Medicine, 2021,27(12):896-904.

Kang-ning LI, Ying-ying ZHANG, Ya-nan YU, et al. Met-Controlled Allosteric Module of Neural Generation as A New Therapeutic Target in Rodent Brain Ischemia^*[J]. Chinese Journal of Integrative Medicine, 2021,27(12):896-904.
Kang-ning LI, Ying-ying ZHANG, Ya-nan YU, 等. Met调控的变构神经再生模块作为治疗鼠脑缺血的新靶点[J]. Chinese Journal of Integrative Medicine, 2021,27(12):896-904. DOI： 10.1007/s11655-019-3182-8.

Kang-ning LI, Ying-ying ZHANG, Ya-nan YU, et al. Met-Controlled Allosteric Module of Neural Generation as A New Therapeutic Target in Rodent Brain Ischemia^*[J]. Chinese Journal of Integrative Medicine, 2021,27(12):896-904. DOI： 10.1007/s11655-019-3182-8.

摘要

目的:

研究Met调控的神经再生变构模块(AM) 作为脑缺血的潜在治疗靶点.

方法:

采用马尔可夫聚类算法(MCL) 对相关目标网络中的功能模块进行挖掘. 根据拓扑相似性预测黄芩苷(BA) 、栀子苷(JA) 、胆酸(CA) 各功能模块

并与IR模型模块进行比较. 该功能模块包括三个基因:Inppl1、Met和Dapk3 (IMD)

通过GO富集分析

得到与该功能模块相关的生物学过程

该功能模块参与神经元的再生. Western blotting研究了IMD的化合物依赖性调控

用免疫共沉淀法揭示三个成员之间的关系

采用IF法测定复合治疗组与缺血再灌注组新生神经元数量

VEGF和MMP-9的表达可能反映了脑缺血后神经生成的变化情况.

结果:

与IR模型组比较

复合治疗组梗死体积明显减小

病理改变明显(

0.05). 研究发现

Inppl1-Met-Dapk3 (IMD) 一个新模块中的三个节点发挥不同的化合物依赖的缺血特异性兴奋性调节活动

在体内成功验证了一种抗缺血神经元生成的兴奋变构模块(AME-GN). BJC治疗组新生神经元增加(

0.05)

与IR模型组比较

复合治疗组VEGF、MMP-9表达降低(

0.05).

结论:

AME证明了我们的开创性方法在发现治疗靶点方面的有效性

这种发现AM的新方法旨在识别治疗靶点

有望加速阐明脑缺血的潜在药理学机制.

Abstract

Objective:

To investigate a Met-controlled allosteric module (AM) of neural generation as a potential therapeutic target for brain ischemia.

Methods:

We selected Markov clustering algorithm (MCL) to mine functional modules in the related target networks. According to the topological similarity

one functional module was predicted in the modules of baicalin (BA)

jasminoidin (JA)

cholic acid (CA)

compared with I/R model modules. This functional module included three genes: Inppl1

Met and Dapk3 (IMD). By gene ontology enrichment analysis

biological process related to this functional module was obtained. This functional module participated in generation of neurons. Western blotting was applied to present the compound-dependent regulation of IMD. Co-immunoprecipitation was used to reveal the relationship among the three members. Immunofluorescence staining was used to determine the number of newborn neurons between compound treatment group and ischemia/reperfusion (I/R) group. The expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) were supposed to show the changing circumstances for neural generation under cerebral ischemia.

Results:

Significant reduction in infarction volume and pathological changes were shown in the compound treatment groups compared with the I/R model group (

0.05). Three nodes in one novel module of IMD were found to exert diverse compound-dependent ischemic-specific excitatory regulatory activities. An anti-ischemic excitatory allosteric module (AM

) of generation of neurons (AM

-GN) was validated successfully

in vivo

. Newborn neurons increased in BJC treatment group (

0.05). The expression of VEGF and MMP-9 decreased in the compound treatment groups compared with the I/R model group (

0.05).

Conclusions:

demonstrates effectiveness of our pioneering approach to the discovery of therapeutic target. The novel approach for AM discovery in an effort to identify therapeutic targets holds the promise of accelerating elucidation of underlying pharmacological mechanisms in cerebral ischemia.

关键词

Keywords

allosteric moduleInppl1-Met-Dapk3generation of neuronsbrain ischemia

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