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Application of TRAF-associated NF-[Kappa]B activator (TANK) and inhibitors thereof in treatment of cardiac hypertrophy

A technique for cardiac hypertrophy and inhibitor, which is applied in the field of gene function and application, can solve problems such as limited treatment methods, and achieve the effects of worsening cardiac function, promoting fibrosis, and promoting cardiac hypertrophy.

Active Publication Date: 2017-02-01
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the mechanism of cardiac hypertrophy is not fully understood and treatment options are limited

Method used

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  • Application of TRAF-associated NF-[Kappa]B activator (TANK) and inhibitors thereof in treatment of cardiac hypertrophy
  • Application of TRAF-associated NF-[Kappa]B activator (TANK) and inhibitors thereof in treatment of cardiac hypertrophy
  • Application of TRAF-associated NF-[Kappa]B activator (TANK) and inhibitors thereof in treatment of cardiac hypertrophy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Example 1 Construction of Heart-specific TANK Gene Knockout Mice and TANK Transgenic Mice

[0050] 1. Construction of heart-specific TANK gene knockout mice (for construction strategy see figure 1 )

[0051] Construction of cardiac-specific TANK gene knockout mice using CRISPR-Cas9 technology. First, design a CRISPR targeting site in intron 2 and 3 of the mouse TANK gene through the online CRISPR design tool (http: / / crispr.mit.edu). The target sequences are:

[0052] TANKs gRNA1: ggAAAAATAGTGTCAAACTGTTGAC TGG,

[0053] TANK sgRNA2: gGCAGGGTTTCTCTGTTATAGCCC TGG.

[0054] In addition, a donor vector (Donor Vector) for homology repair was designed, which includes homology arms on both sides, exon 3 in the middle and two loxp sequences in the same direction.

[0055] (1) Construction of the targeting vector: the two primers corresponding to sgRNA1 and sgRNA2 were fused into double-stranded DNA, and then ligated into the pUC57-sgRNA vector treated with restriction endonu...

Embodiment 2

[0078] The acquisition of embodiment 2 myocardial hypertrophy model

[0079] 1. Grouping of experimental animals: The myocardial hypertrophy model was established by aortic coarctation (AB). Randomly divided into 10 groups, grouped as follows: control group mice sham operation group (α-MHC-MCM Sham, TANK-flox Sham) and control group AB operation group (α-MHC-MCM AB, TANK-flox AB), TANK Gene knockout mouse sham operation group (TANK-KO Sham) and AB operation group (TANK-KOAB), non-transgenic mouse sham operation group (NTG Sham) and AB operation group (NTG AB), heart-specific TANK transgenic mice Sham operation group (TG Sham) and AB operation group (TG AB).

[0080] 2. The myocardial hypertrophy model adopts aortic arch coarctation surgery, and the operation process of the model is as follows:

[0081] 2.1 Preoperative preparation

[0082] (1) Anesthesia: weigh the mice first, calculate the required amount of anesthetic (3% pentobarbital sodium) according to 90 mg / kg body w...

Embodiment 3

[0089] Example 3 Detection of cardiac hypertrophy and fibrosis in myocardial hypertrophy model mice

[0090] 1. Take materials

[0091] (1) Preliminary work: prepare in advance a urine cup filled with 20 mL of 10% formaldehyde by volume, and label it (mouse number, group, type of operation and date of collection). Place a petri dish filled with 10% KCl solution in mass fraction at the sampling site. Turn on the analytical balance and set it to zero for later use. Mice were then weighed and sacrificed.

[0092] (2) Material collection: Ophthalmic curved tweezers clamped the vascular pedicle below the atrial appendage, cut off the heart, and quickly placed it in 10% KCl solution by mass fraction. After the heart stops beating in the diastolic phase, place it on sterilized gauze, gently squeeze the fluid in the heart cavity, dip the surface fluid dry, weigh and record, put the heart into the corresponding urine cup, fix it for 48 hours and use it for pathological testing.

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Abstract

The invention discloses application of a TRAF-associated NF-[Kappa]B activator (TANK) and inhibitors thereof in treatment of cardiac hypertrophy and belongs to the field of functions and application of genes. According to the application, the interrelationship between the expression of a TANK gene and the cardiac hypertrophy is determined; through inhibiting the expression of the TANK, the hypertrophy and fibrosis of cardiac muscles are inhibited remarkably, and cardiac functions are improved; and through promoting the expression of the TANK, the hypertrophy and fibrosis of the cardiac muscles are promoted remarkably, and the cardiac functions are deteriorated. Therefore, the TANK can be used for screening drugs for protecting the cardiac functions, preventing, relieving and / or treating the cardiac hypertrophy and resisting cardiac fibrosis as a drug target, and the inhibitors of the TANK can be used for preparing drugs for protecting the cardiac functions, preventing, relieving and / or treating the cardiac hypertrophy and resisting the cardiac fibrosis.

Description

technical field [0001] The invention belongs to the field of gene function and application, in particular to the application of TANK (TRAF-bound NF-κB activator) as a drug target in the screening of drugs for the treatment of myocardial hypertrophy, and the use of TANK inhibitors in the preparation of drugs for the treatment of myocardial hypertrophy application. Background technique [0002] Cardiac hypertrophy refers to the increase in heart volume and mass that occurs when the heart is stimulated by pressure load or volume load, and its main features are increased volume, weight, and extracellular matrix of cardiomyocytes [1]. As a compensatory mechanism, myocardial hypertrophy is beneficial to maintain normal cardiac function at the initial stage, but long-term continuous stimulation can cause decompensation, leading to dilated cardiomyopathy, heart failure, and even sudden death[2]. Studies have shown that with the occurrence and development of left ventricular hypertr...

Claims

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Application Information

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IPC IPC(8): A61K49/00C12Q1/02A61K45/00A61P9/00
CPCA61K45/00A61K49/0008G01N33/5008G01N33/5023
Inventor 李红良张晓晶张鹏
Owner WUHAN UNIV
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