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Interferon regulatory factor 9 (IRF9) and application of inhibitor thereof in cerebral apoplexy

A technology of stroke and inhibitors, applied in nervous system diseases, cardiovascular system diseases, gene therapy, etc.

Active Publication Date: 2014-04-30
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A variety of neuroprotective drugs have achieved exciting results in animal experiments, but after entering the third phase of clinical trials for stroke, most of them failed to achieve the expected effect. One of the primary reasons for their failure is that most of the known The neuroprotective mechanism works within 4-6 hours after stroke, but it is difficult to implement treatment within such a short time window in clinical practice, so further elucidate the molecular mechanism that promotes or protects brain tissue damage for a long period of time after stroke occurs It is of great significance for the study of effective stroke treatment targets or strategies

Method used

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  • Interferon regulatory factor 9 (IRF9) and application of inhibitor thereof in cerebral apoplexy
  • Interferon regulatory factor 9 (IRF9) and application of inhibitor thereof in cerebral apoplexy
  • Interferon regulatory factor 9 (IRF9) and application of inhibitor thereof in cerebral apoplexy

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] [Example 1] Construction of nerve-specific IRF9 transgenic mice

[0039] The construction process of IRF9-flox mice:

[0040] Transgenic vector construction information: Use the upstream primer, namely 5'-CCAGATTACGCTGATATGGCATCAGGCAGGGCACG-3' (SEQ ID NO. 1); the downstream primer, 5'-AGGGAAGATCTTGATTCAGCAGGCTCTACACAGGG-3' (SEQ ID NO. 2), to amplify the full length of mouse IRF9 Gene (NCBI, Gene ID: 16391, NM_001159417.1), insert the cDNA into the pCAG-CAT-LacZ vector, which contains a CMV enhancer and a promoter of chicken β-actin gene (CAG, chicken β-actin gene) and connected to the chloramphenicol acetyltransferase gene (CAT, chloramphenicol acetyltransferase), the loxP site is located on both sides of the CAT, and the expression of IRF9 in nerve cells is driven by the CAG promoter ( figure 1A). IRF9-floxed mice: The constructed pCAG-IRF9-CAT-LacZ vector was constructed into fertilized embryos (C57BL / 6J background) by microinjection to obtain IRF9-floxed mice. Neu...

Embodiment 2

[0044] [Example 2] Acquisition of mouse cerebral infarction model (I / R)

[0045] 1. Grouping of experimental animals: male C57BL / 6 strain wild-type mice, IRF9 knockout mice, brain-specific IRF9 transgenic mice and non-transgenic mice, cerebral infarction model was established by middle cerebral artery ischemia-reperfusion (I / R). Randomly divided into 8 groups, 10 mice in each group: C57BL / 6 strain wild-type mice sham operation group (WT SHAM) and I / R operation group (WT I / R), IRF9 gene 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), nerve cell-specific IRF9 transgenic mouse sham Surgery group (TG SHAM) and I / R surgery group (TG I / R).

[0046] 2. The I / R operation of cerebral infarction by suture method adopts the MCAO (middle cerebral artery occlusion, middle cerebral artery occlusion) model operation process:

[0047] (1) Grab the mouse, use 3% isofluran...

Embodiment 3

[0053] [Example 3] Determination of cerebral infarction volume in cerebral infarction model (I / R) mice

[0054] The evaluation indicators of the severity of cerebral ischemia / reperfusion injury mainly include cerebral infarct volume and neurological function score, and these indicators are positively correlated with the severity of ischemia / reperfusion injury.

[0055] (1) Neurological function and behavioral scores were performed 24h, 72h, and 7d after surgery before sampling;

[0056] Improved method based on Berderson neurological function score (9-point scale):

[0057] 0 points: no symptoms of nerve damage;

[0058] 1 point: The contralateral forelimb is curled up when the tail is raised, or the forelimb on the affected side cannot be fully reached;

[0059] 2 points: The opposite shoulder is adducted when the tail is raised;

[0060] 3 points: flat push: the resistance decreases when pushing to the opposite side;

[0061] 4 points: can move spontaneously in all direc...

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Abstract

The invention discloses interferon regulatory factor 9 (IRF9) and application of an inhibitor thereof in cerebral apoplexy, belonging to the field of gene function and application. The invention uses IRF9 gene knock-out mice and brain-specific IRF9 transgenic mice as experimental subjects and adopts middle cerebral artery ischemia reperfusion model, results show that compared with mild type C57 mouse, the brain infarction volume of IRF9 gene knock-out mouse is apparently inhibited, and nerve function is improve remarkably, while the infarction volume of nerve-specific IRF9 transgenic mouse is apparently inhibited, and nerve function is deteriorated markedly. Therefore, IRF9 gene has nervous system function deterioration effect; especially, IRF9 gene can deteriorate cerebral apoplexy. As for the above function of IRF9, the invention provides application of IRF9 as drug target of cerebral apoplexy treatment in developing medicaments for treating cerebral apoplexy.

Description

[0001] technical field [0002] The invention belongs to the field of gene function and application, and particularly relates to the application of an interferon regulatory factor 9 (IRF9) and its inhibitor in stroke diseases. [0003] Background technique [0004] Ischemic stroke is currently the fourth leading cause of death and the second leading cause of disability in the world. Ischemic stroke can cause irreversible brain damage within minutes to hours after its onset, causing serious harm to the life and health of patients. Neuron cells are an important part of the central nervous system, but their high metabolic rate reduces their tolerance to ischemic and hypoxic environments, so they are more susceptible to damage than other neurovascular components. Currently, tissue plasminogen activator (tPA) fibrinolytic therapy is still the main treatment for ischemic stroke, but its time window of only 4.5 hours limits most patients to receive only symptomatic treatment. Stu...

Claims

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Application Information

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IPC IPC(8): A61K48/00A61K39/395A61P9/10A61P25/00C12Q1/68
Inventor 李红良张晓东向梅郭森卢燕云蒋曦
Owner WUHAN UNIV
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