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Application of TNF receptor-related factor 1 (tarf1) and its inhibitors in liver ischemic diseases

A related factor, liver ischemia technology, applied in cardiovascular system diseases, antibodies, gene therapy, etc.

Active Publication Date: 2016-11-30
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although other TRAF family members are widely distributed in different tissue cells, TRAF1 mRNA can only be detected in a few tissues such as spleen, lung, and testis

Method used

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  • Application of TNF receptor-related factor 1 (tarf1) and its inhibitors in liver ischemic diseases
  • Application of TNF receptor-related factor 1 (tarf1) and its inhibitors in liver ischemic diseases
  • Application of TNF receptor-related factor 1 (tarf1) and its inhibitors in liver ischemic diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] [Example 1] Construction of hepatocyte-specific TRAF1 transgenic mice

[0037]To further study the effect of TRAF1 overexpression on liver ischemia / reperfusion injury, we constructed several hepatocyte-specific TRAF1 transgenic mice (TRAF1-TG). Transgenic vector construction information: use TRAF1 gene upstream primer, namely 5'-GAACTCGAGCCACCATGGCCTCCAGCTCAGCCCC-3' (SEQ ID NO.1); TRAF1 gene downstream primer, namely 5'-GAATGCGGCCGCCTAAGCACTAGTGTCCACAA-3' (SEQ ID NO.2), amplify small Mouse TRAF1 full-length gene (NCBI, Gene ID: 22029, XM_006497845.1), insert the cDNA into the pGEM-T vector (Promega company product, product number A1360) downstream of the Albumin promoter, and construct the constructed vector into a fertilized embryo by microinjection (C57BL / 6 background), and hepatocyte-specific TRAF1 transgenic mice were obtained. Genomic DNA was obtained from transgenic mice by cutting their tails, and identified by PCR to detect the structure of the exogenous gene. ...

Embodiment 2

[0040] [Example 2] Mouse liver ischemia-reperfusion injury model (ischemia / reperfusion injury, I / R) was obtained

[0041] 1. Grouping of experimental animals: male C57BL / 6 strain wild-type mice, TRAF1 knockout mice, TRAF1 transgenic mice and non-transgenic mice, liver ischemia model was established by liver ischemia-reperfusion (I / R). They were randomly divided into 8 groups: C57BL / 6J strain wild-type mice sham operation group (WT SHAM) and I / R operation group (WT I / R), TRAF1 knockout mouse sham operation group (KO SHAM) and I / R operation group (KO I / R), non-transgenic mouse sham operation group (NTG SHAM) and I / R operation group (NTG I / R), liver cell-specific TRAF1 transgenic mouse sham operation group (TG SHAM) and I / R surgery group (TG I / R).

[0042] 2. I / R operation of the liver ischemia-reperfusion injury model (using non-invasive vascular clips to clamp the portal vein and hepatic artery in the middle lobe and left lobe, so that about 70% of the liver ischemia) model o...

Embodiment 3

[0048] [Example 3] Determination of liver necrosis area and liver function index

[0049] The evaluation indicators of the severity of liver ischemia / reperfusion injury mainly include the area of ​​liver necrosis and liver function indicators (AST, ALT), all of which are positively correlated with the severity of liver ischemia / reperfusion injury.

[0050] 1. Take materials

[0051] Mice were killed by cervical dislocation in the sham operation group (Sham) and at 12h, 24h, and 48h after ischemia-reperfusion, and 1 mL of blood was collected from the inferior vena cava immediately to separate the serum. At the same time, the left lobe of the liver in the ischemic area with a size of about 1.5cm×1cm×0.2cm was fixed in 10% neutral formalin for 24 hours, dehydrated, embedded, paraffin-sectioned, and HE stained. (Separation of serum: the EP tube that collected the blood was left at room temperature for 1-2 hours to allow the blood to coagulate naturally. Centrifuge at 4°C for 30 m...

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Abstract

The invention discloses the application of a TRAF1 inhibitor in liver ischemic diseases, and belongs to the field of biomedicine. In the present invention, TRAF1 gene knockout mice and hepatocyte-specific TRAF1 transgenic mice are used as experimental objects, and the hepatic ischemia-reperfusion injury model is used. The results show that compared with wild-type C57 mice, TRAF1 gene knockout mice have obvious liver necrosis Inhibited, liver function also significantly improved, while hepatic cell-specific TRAF1 transgenic mice had significantly increased liver necrosis and significantly worsened liver function. Therefore, TRAF1 gene has the effect of deteriorating liver function, especially TRAF1 gene can aggravate hepatic ischemic disease. According to the above functions of TRAF1, TRAF1 is provided as a drug target for the treatment of liver ischemic diseases and applied in the development of drugs for liver ischemic diseases.

Description

technical field [0001] The invention belongs to the field of gene function and application, and in particular relates to the application of tumor necrosis factor (TNF) receptor-associated factor 1 (TNF receptor-associated factor 1, TRAF1) as a drug target in the screening of drugs for the treatment of liver ischemic diseases. As well as the application of TRAF1 inhibitors in the preparation of drugs for treating hepatic ischemic diseases. Background technique [0002] Ischemia / reperfusion injury (I / R) is one of the hot issues in current research. The mechanism is quite complex and many factors are involved. Current theoretical research and clinical practice have confirmed that when the blood supply is blocked for more than 30 minutes, it will cause changes in the ultrastructure and dysfunction of various organelles, resulting in irreversible damage and even death of cells. Timely restoration of blood supply is regarded as saving this part of the tissue. important measures....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K48/00A61K39/395A61P1/16A61P9/10C12Q1/68
Inventor 李红良张晓东张晓飞张艳蒋丁胜刘小熊
Owner WUHAN UNIV
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