Application of NRG1 (neuregulin1)-ERBB4 complex in preparing medicaments for treating myocardial ischemia

A NRG1-ERBB4, myocardial ischemia technology, applied in the field of gene and protein function and application, can solve problems such as difficulty in administration time and interval, large trauma, and prone to rejection.

Inactive Publication Date: 2015-09-23
连祺周
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Existing treatment methods have their limitations: for example, coronary artery revascularization cannot avoid myocardial injury, and 20-37% of patients are complicated by myocardial infarction, and symptoms such as heart failure gradually appear; while heart transplantation is limited in donors, Large trauma, prone to complications such as rejection
Although these research results all suggest that NRG1 is expected to become an effective means of treating myocardial infarction, it also has its shortcomings: first, the half-life of NRG1 in vivo is extremely short (about 30 minutes), which makes it difficult to formulate the administration time and interval; Second, only about 10% of cardiomyocytes in the adult heart are mononuclear cells, and only 0.3% of mononuclear myocytes respond to NRG1 stimulation and re-enter the division cycle [Bersell, K., et al., Neuregulin1 / ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell, 2009.138(2): p.257-70.]; Third, the stimulation of NRG1 is receptor-dependent, and whether the target cells express ERBB receptors determines whether they respond to NRG1 reaction

Method used

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  • Application of NRG1 (neuregulin1)-ERBB4 complex in preparing medicaments for treating myocardial ischemia
  • Application of NRG1 (neuregulin1)-ERBB4 complex in preparing medicaments for treating myocardial ischemia
  • Application of NRG1 (neuregulin1)-ERBB4 complex in preparing medicaments for treating myocardial ischemia

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: lentivirus preparation, MSC infection and identification of ERBB4 expression efficiency

[0031] The third-generation lentiviral packaging plasmid required for this experiment was purchased from Addgene (https: / / www.addgene.org / ), see the plasmid map Figure 1A . Shuttle plasmids pGFP and pER4-GFP were purchased from Guangzhou Funeng Gene Co., Ltd., see the plasmid map Figure 1B . See Table 1 for information on these plasmids. Lentiviral packaging cells 293FT were purchased from Invitrogen (catalogue number R700-07); MSCs were extracted from bone marrow of C57 / BL6 mice. C57 / BL6 mice were purchased from the Experimental Animal Center of the University of Hong Kong.

[0032] Table 1: Lentiviral Packaging Plasmid Information

[0033]

[0034] The reagents required for this experiment are listed in Table 2.

[0035] Table 2: Reagents used for lentivirus preparation, MSC infection and ERBB4 expression efficiency identification

[0036]

[0037] The co...

Embodiment 2

[0057] Example 2. Detecting the anti-apoptotic ability of MSC-ERBB4 and MSCe in hypoxic environment

[0058] The purpose of this experiment is to detect whether activation of the NRG1-ERBB4 pathway in MSCs affects the anti-apoptotic ability of cells in a hypoxic environment.

[0059] One of the changes on the surface of the cell membrane is the transfer of phosphatidylserine (PS) from the inside of the cell membrane to the outside of the cell membrane, exposing PS on the outer surface of the cell membrane. Annexin V is a Ca+-dependent phospholipid-binding protein that readily binds to phospholipids such as PS. Utilizing the high affinity of Annexin V to PS, Annexin V can be used as a probe to detect PS exposed on the surface of the cell membrane, thereby distinguishing cells in apoptotic state. However, PS translocation outside the cell membrane is not unique to apoptotic cells and can also occur in necrotic cells. The difference between apoptosis and necrosis is the integri...

experiment example 3

[0063] Experimental example 3. Detection of the expression difference of NRG1 in MSC-ERBB4 and MSCe

[0064] Proteins and culture supernatants of MSC, MSCe and MSC-ERBB4 were collected.

[0065] The protein extraction was carried out using RIPA (Sigma, catalog number R0278) reagent according to the instructions.

[0066] The collection steps of the cell culture supernatant: inoculate MSC, MSCe and MSC-ERBB4 on 10cm culture dishes respectively, adjust the cell density to 70%-80%, wash the cells twice with PBS, add 8mL phenol red-free DMEM (GIBCO, catalog number 21063-029). The cells were cultured under normoxia and hypoxia for 24 hours, and then the cell supernatant was collected, and the residual cells were removed by centrifugation and 0.22 μm filter membrane, and the supernatant was concentrated with concentrated injection (Millipore, catalog number UFC801024). The concentration factor is 10.

[0067] The resulting cellular protein was quantified by the Bradford (BIO-RAD, c...

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Abstract

The invention provides an application a complex (NRG1-ERBB4 complex) of NRG1 (neuregulin1) and a tyrosine kinase receptor ERBB4 thereof in preparing medicaments for treating myocardial ischemia. The invention provides a medicament for treating the myocardial ischemia by using the NRG1-ERBB4 complex as a target. Preferably, the medicament is mesenchymal stem cells (MSC) modified by ERBB4 genes. ERBB4 is over-expressed in the MSC by lentivirus, and therefore, the expression of a ligand NRG1 of the ERBB4 is up-regulated in a feedback manner so as to form a medicament having an NRG1-ERBB4-NRG1 self-feedback channel, so that not only is the endurance capacity of the MSCC on an oxygen-deficient environment improved, but also the concentration of high-level NRG1 is kept by means of the NRG1-ERBB4-NRG1 self-feedback channel, a protection role of the MSC on myocardial cells is improved and enhanced, and a curative effect of the medicament for treating the myocardial ischemia is improved.

Description

technical field [0001] The invention belongs to the field of functions and applications of genes and proteins, and relates to the application of neuregulin 1 (NRG1) and its tyrosine protein kinase receptor ERBB4 complex (NRG1-ERBB4 complex), in particular to the application of NRG1-ERBB4 complex in Application in preparation of medicine for treating myocardial ischemia. Background technique [0002] According to statistics, the incidence of cardiovascular disease ranks first among non-communicable diseases in the world. , is a disease that seriously threatens human health. Although great progress has been made in the prevention, diagnosis and treatment of cardiovascular disease in recent years, its morbidity and mortality are still high. Existing treatment methods have their limitations: for example, coronary artery revascularization cannot avoid myocardial injury, and 20-37% of patients are complicated by myocardial infarction, and symptoms such as heart failure gradually...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K35/28A61P9/10
Inventor 连祺周梁小婷
Owner 连祺周
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