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Application of Isl1 gene or protein in sinoatrial node abnormality related diseases

A gene and protein technology, applied in the field of diagnosis and treatment of congenital heart disease, can solve the problems of limited number of pacemaker cells, difficult separation and purification, and difficulty in distinguishing the structure of pacemaker cells.

Pending Publication Date: 2015-02-11
SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0006] But relatively speaking, because the deletion of known pacing-related genes will cause a large number of early death of embryos, the pacemaker cells are also difficult to distinguish in terms of tissue structure, and the number of pacing cells is limited, so it is difficult to separate and purify. There is very limited understanding of the cardiac pacing conduction system, especially the mechanisms regulating the formation and function of cardiac pacemaker cells

Method used

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  • Application of Isl1 gene or protein in sinoatrial node abnormality related diseases
  • Application of Isl1 gene or protein in sinoatrial node abnormality related diseases
  • Application of Isl1 gene or protein in sinoatrial node abnormality related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1I

[0132] Example 1Isl1 and HCN4 are expressed in cardiac SAN cells

[0133] In order to study the role of Isl1 in the formation and function of SAN, the expression of Isl1 during SAN development was first analyzed, and several SAN cell and atrial cardiomyocyte antibodies (HCN4Tbx3Cx40 purchased from abcam company) were used as markers.

[0134] HCN4 is a pacemaker cell channel protein, which begins to express in the early heart development and plays a key role in the differentiation and development of SAN. At E9.5, Isl1 is expressed in the sinus venosus (SV) of the myocardium, and HCN4 is highly expressed in the germinal region of pacemaker cells in early embryos ( figure 1 A).

[0135] At E10.5, Isl1 and HCN4 were co-expressed in the embryonic SAN head ( figure 1 B) and tail ( figure 1 C), the venous valve (vv), and the atrial myocardium (DM) surrounding the vestibular mesentery ( figure 1 A, B, arrows).

[0136] During late embryonic development and early postnatal period...

Embodiment 2

[0140] Example 2 Reduction of Isl1 expression in Isl1 compound mutant mouse embryos leads to reduction of sinus arrhythmia and SAN cells

[0141] 2.1 Construction of an Isl1 compound mutant mouse model with incomplete expression of Isl1 (Isl1nLacZ / f Neo+ ), its phenotype is milder than that of whole-body knockout mice, and it can survive for a little longer (death at E12.5), but its phenotype is heavier than that of Isl1 incompletely expressed mice.

[0142] The Isl1 compound mutant mouse model uses the Isl1 nuclear LacZ knock-in mouse line (Isl-nLacZ), and the Isl1 low expression mouse line (Isl1f neo / +, the mouse Isl1 intron contains neomycin site, which can interfere with the normal expression of Isl1).

[0143] Results: Isl1 complex mutant mice (Isl1nLacZ / f neo ) expresses lower amounts of Isl1 than the Isl1-incomplete mouse line and causes embryonic death at E11.5 (54). X-gal staining of tissue sections showed that the color development of Isl1-nLaz in Isl1-nLaz mice ...

Embodiment 4I

[0156] Example 4Isl1 is still essential to differentiated cardiomyocytes

[0157] In Isl1 compound mutant embryos, the expression of Isl1 in differentiated SAN pacemaker cells (E9.5-E11.5), cardiac progenitor cells in the second heart region, and SV, SAN myocardium were all significantly reduced. Therefore, Troponin-Cre (cTnT-Cre) mice were used to specifically knock out Isl1 in differentiated cardiomyocytes to observe the role of Isl1 in differentiated sinus node cells.

[0158] The phenotype of cTnT-Cre knockout Isl1 mice (cTnT-Cre; Isl1 mouse line) is similar to that of Isl1 compound mutant mice. The mutant mice die at the early embryonic stage at E9.5-E11.5. Marked slow heart rate and premature beats, see Figure 7 .

[0159] Conclusion: The experiments showed that the expression of Isl1 is still required for the pacing function of cardiomyocytes even after they have matured.

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Abstract

The invention provides an application of Isl1 gene or protein in sinoatrial node abnormality related diseases, concretely provides a use of an LIM homodomain transcription factor (Isl1) gene or its protein in the preparation of a reagent or kit for detecting or predicting the sinoatrial node (SAN) abnormality related diseases, and also provides a method for detecting or predicting the sinoatrial node abnormality related diseases. The Isl1 gene or protein can be used in prenatal screening and diagnosis of various kinds of congenital heart diseases with arrhythmia as the main symptoms, so it is in favor of realizing prenatal and postnatal care.

Description

technical field [0001] The invention relates to the field of diagnosis and treatment of congenital heart disease, in particular, the invention relates to the application of Isl1 gene and protein in the diagnosis of diseases related to abnormal sinus node. Background technique [0002] The cardiac pacing conduction system is a special myocardial tissue that generates and propagates electrical impulses and plays an important role in regulating the rhythmic contraction of the heart. Abnormalities in the development and function of the pacing conduction system can lead to arrhythmias and sudden cardiac death. [0003] In China, more than 500,000 cases of sudden cardiac death occur every year. Arrhythmia is the leading cause of sudden cardiac death. [0004] The cardiac pacing conduction system consists of the pacemaker (sinus node / SAN), atrioventricular node (AVN) and Purkinje fibers. In mice, cardiac inflow tracts begin to register pacing signals at embryonic day 8 (E8.0). ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68G01N33/68A01K67/027
CPCC12Q1/6883A01K67/02C12Q2600/156C12Q2600/158G01N33/6893G01N2800/32
Inventor 孙云甫梁兴群
Owner SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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