CN111840515A - Medical application of CREG protein in megakaryocyte maturation differentiation thrombopoiesis - Google Patents
Medical application of CREG protein in megakaryocyte maturation differentiation thrombopoiesis Download PDFInfo
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Abstract
The invention relates to a medical application of E1A activated gene repressor (CREG) protein, and relates to a medical application of CREG protein in the promotion of platelet generation through megakaryocyte maturation and differentiation. Use of a CREG protein in the manufacture of a medicament for the prevention and/or treatment of a hematological disorder. Use of an agent for detecting the expression level of a CREG protein in the manufacture of a kit for diagnosis of a disease in the blood system. Experiments prove that the CREG gene knockout mouse bone marrow megakaryocyte maturation obstacle and polyploidization are hindered. At a cytological level, the expression level of CREG is gradually increased in the maturation of Dami cells; the reduction of CREG can significantly affect the expression of the megakaryocyte-specific marker protein CD41a/CD62P and the cellular polyploid process is impaired. The exogenous recombinant CREG protein can promote the process of cell polyploidization and improve the expression of CD41a/CD 62P. The C/EBP beta is combined with a CREG protein promoter region to regulate the expression of CREG. Therefore, CREG proteins are able to promote the mature differentiation of megakaryocytes and possibly the production of platelets.
Description
Technical Field
The invention relates to a medical application of E1A activated gene repressor (CREG) protein, relates to a medical application of CREG protein in megakaryocyte maturation differentiation thrombopoiesis promotion, and particularly relates to an application of CREG protein in preparation of a drug with a definite protection effect on megakaryocyte maturation differentiation thrombopoiesis promotion.
Background
Clinical studies have found that severe clinical symptoms are caused by the mature and differentiated megakaryocyte disorders in hematological diseases such as Idiopathic Thrombocytopenic Purpura (ITP), myelodysplastic syndrome (MDS) and acute megakaryocyte leukemia, which are caused by the decrease of platelets in patients to various degrees. Megakaryocyte maturation disorders are mainly manifested by normal or increased bone marrow megakaryocyte numbers, but thrombocytopenia is caused by metakaryotic megakaryocytes. Megakaryocytes are the only polyploid cells in bone marrow and are mainly responsible for the generation of platelets and the participation in important functions such as blood coagulation, and the polyploid state of the cells is closely related to the quality and quantity of produced platelets. Mature megakaryocytes are derived from hematopoietic stem cells by differentiation from megakaryolineage progenitor cells, primitive megakaryocytes, naive megakaryocytes, and granular megakaryocytes. During the mature and differentiation process of megakaryocytes, the cell volume and chromosome ploidy are increased, and a platelet boundary membrane system gradually appears. Megakaryocyte maturation and differentiation are regulated by many factors, and the pathogenesis of the disorder of maturation and differentiation is still not well understood. Therefore, the molecular mechanism causing megakaryocyte maturation and differentiation disorder is better understood, and a new therapeutic target and clinical basis are provided for preventing and treating thrombocytopenia.
An E1A activated gene Repressor gene (CREG) is a novel glycoprotein with small molecular weight, and early researches find that CREG is widely expressed in differentiated mature tissues, particularly high expression in circulating tissues such as cardiac muscle, blood vessels and the like, and suggest that CREG can be involved in the maintenance of tissue differentiation homeostasis. The inventors have worked on studies of the homeostasis of the cardiovascular system by CREG since 2000. Research finds that the CREG can reduce vascular endothelial cell inflammatory injury, resist the occurrence and development of atherosclerosis and vascular remodeling, can remarkably delay myocardial fibrosis and improve cardiac function by regulating myocardial cell autophagy and apoptosis, and the Research results are successively published in ATVB, Cardiovasular Research, BBA and other magazines, and the CREG is a key regulation factor for maintaining Cardiovascular homeostasis and is involved in regulating and controlling the occurrence and development of Cardiovascular diseases.
The inventor has found through experimental study that: (1) CREG is abundantly expressed in human and mouse megakaryocytes; (2) creg-/-Megakaryocytes in the bone marrow of mice are hampered by the process of polyploidization due to loss of CREG; (3) the Dami cell line gradually differentiated under stimulation of PMA, CD41a/CD62P was up-regulated at mRNA and protein level, CREG was also up-regulated at mRNA and protein level; (4) knockdown of CREG in the Dami cell line resulted in decreased expression of CD41a/CD62P and impaired cell polyploidization. (5) C/EBP beta in the Dami cell line is an important molecule for regulating CREG to promote the maturation and differentiation of Dami cells.
Therefore, the inventors propose a study hypothesis: CREG regulates the mature differentiation of megakaryocytes and promotes the generation of platelets. To verify this hypothesis, the inventors studied the maturation of bone marrow megakaryocytes in CREG knockout mice, as well as the number and function of platelets; the molecular mechanism of CREG in regulating the mature differentiation of megakaryocytes and promoting thrombopoiesis is studied in Dami cells. The completion of the research can provide new targets and experimental basis for the treatment of thrombocytopenia.
Disclosure of Invention
The invention aims to provide the medical application of CREG protein in the promotion of platelet generation through megakaryocyte maturation and differentiation.
In order to achieve the above object, the present invention adopts the following technical solutions.
Use of the E1A-activated gene repressor (CREG) protein or an active fragment thereof for the preparation of a medicament for the prevention and/or treatment of a disease of the blood system.
Furthermore, the hematologic system diseases are megakaryocyte maturation disorder and thrombocytopenia diseases, including ITP, MDS, acute megakaryocytic leukemia and the like.
Use of CREG protein or active fragments thereof in the preparation of medicaments or inducers for the in vitro artificial culture of platelet production.
The use of recombinant vectors or recombinant cells expressing a CREG protein for the preparation of a medicament for the prevention and/or treatment of hematological disorders; wherein said recombinant cells contain a recombinant vector expressing a CREG protein or an active fragment thereof, said recombinant vector containing a nucleotide sequence encoding a CREG protein or an active fragment thereof.
Further, the recombinant vector is a recombinant adenovirus vector.
Use of an agent capable of inhibiting the down-regulation of CREG protein expression or an active fragment thereof, or an agent that promotes the up-regulation of CREG protein expression or an active fragment thereof, in the manufacture of a medicament for the prevention and/or treatment of a hematological disorder.
The use of CREG protein or active fragments thereof for screening drugs for preventing and/or treating hematological diseases.
Use of an agent for detecting the expression level of a CREG protein or an active fragment thereof for the preparation of a kit for the diagnosis of a disease in the blood system.
A composition comprising a CREG protein or an active fragment thereof, a recombinant vector or a recombinant cell expressing a CREG protein or an active fragment thereof, or an agent capable of inhibiting the down-regulation of the expression of a CREG protein or an active fragment thereof or an agent promoting the up-regulation of the expression of a CREG protein or an active fragment thereof, and optionally a pharmaceutically acceptable carrier or excipient.
Further, the composition is used for preparing a medicament for preventing and/or treating the diseases of the blood system.
In the present invention, the agent capable of inhibiting the down-regulation of CREG protein expression includes, for example, an agent capable of binding to an agent which down-regulates the CREG protein expression level to inhibit the function of the agent. In embodiments of the invention, the agent capable of inhibiting the down-regulation of CREG protein expression is, for example, an agent capable of reducing the reduction of CREG protein in megakaryocyte maturation disorders, in which platelet production is reduced.
In the present invention, the CREG protein (i.e., human E1A activator gene repressor protein, cellular redepressor of E1A-secreted gene) includes both CREG proteins with complete sequences and CREG proteins with partial sequences only, which function as CREG proteins.
In an embodiment of the invention, the GenBank number of the CREG protein is NP _ 003842.1.
In an embodiment of the invention, the GenBank number of the CREG gene is NM — 003581.2.
In an embodiment of the present invention, the recombinant adenovirus vector is human adenovirus type 5 Ad 5-CREG, which was deposited at the China center for type culture Collection (CCTCC, Wuhan university) at 2008/month and 2 with a collection number of CCTCC-V200801. This deposited information is disclosed in chinese patent CN 101475961 a.
In the present invention, the megakaryocyte maturation disorder, namely thrombocytopenia, refers to a megakaryocyte maturation disorder caused by various causes in hematological diseases (including ITP, MDS, acute megakaryocytic leukemia, etc.), resulting in thrombocytopenia and ultimately severe clinical symptoms.
In the present invention, the prevention and/or treatment of a megakaryocyte maturation disorder, thrombocytopenia refers to the inhibition or slowing of the onset, progression, and/or reversal of pathological changes in a megakaryocyte maturation disorder.
In the present invention, the vector is, for example, a prokaryotic expression vector, a eukaryotic expression vector, a phage vector, or a viral vector. Wherein the prokaryotic expression vector is PET vector, PGEX vector, the eukaryotic expression vector is pcDNA3.1, pEGFP-C1, pPIC9K, the phage vector is lambda vector lambda gt, lambda gt-lambda B, and the virus vector is retrovirus, lentivirus, adenovirus or adeno-associated virus vector.
In an embodiment of the present invention, wherein said recombinant vector is a recombinant adenoviral vector.
In an embodiment of the invention, the recombinant adenoviral vector is Ad-CREG-GFP.
In the present invention, the cell may be a prokaryotic cell or a eukaryotic cell. The eukaryotic cell is, for example, a mammalian cell. The cell may be obtained by introducing a recombinant vector into a prokaryotic cell or a eukaryotic cell.
In the present invention, the prokaryotic cell may be, for example, escherichia coli DH5 α, JM109, Top10, etc., the eukaryotic cell may be, for example, CHO cell, 293T cell, vascular smooth muscle cell, etc., and the mammal may be, for example, rat, mouse, dog, mini-pig, monkey, human, etc.
In the present invention, a host cell transfected with a specific nucleic acid or vector can be obtained using any kind of transfection method known in the art, for example, a nucleic acid can be introduced into a cell by electroporation or microinjection; alternatively, lipofection agents such as FuGENE 6, X-treemeGENE and LipofectAmine; alternatively, the nucleic acid may be introduced into the cell by suitable viral vectors based on retroviruses, lentiviruses, adenoviruses and adeno-associated viruses.
In the present invention, the expression level of CREG protein can be detected by methods well known in the art, for example, by amplifying CREG protein mRNA and performing quantitation or Western blot to detect the expression level of CREG protein.
In the present invention, the expression level of the protein refers to the level of mRNA or the level of protein.
In the present invention, the up/down regulation of the expression of a protein in a tissue/cell means increasing or decreasing the protein level or mRNA level in the tissue/cell by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or by more than 100%. Wherein the up-or down-regulation is compared to tissue/cells not pre-treated, e.g., tissue/cells of a transfected control vector group.
Compared with the prior art, the invention has the following beneficial effects.
The invention provides the medical application of CREG protein in the promotion of platelet generation through megakaryocyte maturation and differentiation for the first time. A large number of experiments prove that the CREG gene knockout mouse bone marrow megakaryocyte is hindered in maturation and polyploidization. On a cytological level, the expression level of CREG is gradually increased in the maturation of Dami cells; the reduction of CREG can significantly affect the expression of the megakaryocyte-specific marker protein CD41a/CD62P and the cellular polyploid process is impaired. The exogenous recombinant CREG protein can promote the process of cell polyploidization and improve the expression of CD41a/CD 62P. Further research finds that C/EBP beta is combined with a CREG protein promoter region to regulate the expression of CREG. It can be seen that the CREG protein can promote the mature differentiation of megakaryocytes and possibly promote the generation of platelets.
Drawings
FIG. 1 shows that CD41a/CD62P/CREG mRNA and protein level expression is significantly down-regulated when differentiation is induced by PMA in Dami cells. Wherein, A-C is stimulated with PMA for 0 to 4 days, and the protein level of CD41a/CD62PmRNA and protein level are obviously up-regulated; D-E administration of PMA stimulated for 0 to 4 days, CREG and protein levels were significant.
FIG. 2 shows the expression of CREG detected by immunofluorescence staining.
FIG. 3 is a decrease in CREG causing downregulation of CD41a/CD62P expression by Dami cells, and polyploidization was hindered. Wherein, A-B is expression change of CD41a/CD62P protein after western blotting detection CREG knockdown.
Figure 4 is a flow cytometric assay for CREG knockdown CD41a protein expression.
Figure 5 is a flow cytometric assay for CREG knockdown CD62P protein expression. FIG. 6 is a graph showing the control of CREG by C/EBP β. Wherein A-B is the expression of CREG when western blot detects C/EBP beta knockdown.
FIG. 7 shows the expression of C/EBP detected by immunofluorescence staining.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples and drawings, but those skilled in the art will understand that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
The experimental data of the invention are percentages. The comparison of the two sample rates was performed using the chi-square test, and the statistical processing was performed using the SPSS 17.0 software package. P <0.05 is statistically different.
Example 1 PMA stimulation of Dami cells was followed by measurement of CD41a/CD62P/CREG mRNA and protein level expression.
1. Inducing the maturation differentiation of Dami cells.
Dami cells were stimulated continuously for 4 days with PMA (100 nM) and tested for expression of CD41a/CD62P and for polyploidization of the cells using flow cytometry.
2. RNA level detection of CD41a/CD 62P/CREG.
The expression of CD41a/CD62P/CREG was detected after continuous 4 days of PMA (100 nM) stimulation of Dami cells by RT-PCR. And (3) taking each group of cells, adding 1 ml of Trizol lysate, and extracting total RNA. Human CREG gene RT-PCR primers designed and synthesized based on the human CD41a/CD62P/CREG sequence in GenBank were as follows: human CREG primer.
hCREG-F: 5’-GACTTTGGCACAGACCAACTT-3′(SEQID NO：1)。
hCREG-R: 5′- CAGGGTGTCGAATGAATAACGA-3′(SEQID NO：2)。
GAPDH-F: 5′- GGAGCGAGATCCCTCCAAAAT-3′(SEQID NO：3)。
GAPDH-R: 5′- GGCTGTTGTCATACTTCTCATGG-3(SEQID NO：4)。
The extracted RNA was synthesized into cDNA (first strand cDNA Synthesis kit from Takara, Inc.; amplification conditions were 37 ℃ for 15 min; 85 ℃ for 5 s).
The specific conditions are as follows.
dH2O 9.5 μl。
2 XTaq Master Mix (Kangji Co.) 12.5. mu.l.
Mu.l of upstream primer.
The downstream primer was 1. mu.l.
Mu.l of template cDNA.
95 ℃，3 min。
30 s at 94 ℃; at 59 ℃ for 30 s; 72 ℃, 1 min, 30 cycles.
72 ℃，10 min。
The amplified product is separated and detected by 2% agarose gel, and is developed by EB staining, and a cDNA expression band with the size of about 250 bp can be detected. And (4) prompting by a result: no significant abnormalities in CREG mRNA levels were seen between the two groups, and the results are shown in FIGS. 1-2.
3. The expression change of CD41a/CD62P/CREG protein in the cells is detected by using western blotting.
The expression condition of CD41a/CD62P/CREG protein in each group of cells is detected by adopting a western blotting method. After cracking, the protein concentration in the cracking solution is determined by adopting a BCA colorimetric method kit, 40 mu g of protein is added into 4 XLoadingbuffer and boiled for 8min at 95 ℃, and then the electrophoresis termination time is judged by SDS-PAGE electrophoresis of 10% separation gel. Transferring the sample onto the cellulose membrane at 350mA current for 80 min; blocking in 5% skimmed milk powder diluted with TBS-T at room temperature for 1.5 h, adding primary antibody (anti-CD 41a/CD62P/CREG antibody 1:1000, anti-GAPDH antibody 1: 2000), and incubating at 4 deg.C overnight; placing on a shaking table on the next day, shaking for half an hour, and washing the membrane with TBS-T for 3 times, 15min each time; adding rabbit anti-mouse secondary antibody (1: 1000 dilution), incubating at room temperature for 2 h, washing membrane with TBS-T for 4 times, each time for 20 min, and performing ECL chemiluminescence development. As a result, it was found that: after PMA induces differentiation, the expression level of CD41a/CD62P/CREG protein is obviously increased.
Example 2 reduction of CREG expression following CD41a/CD62P, the process of polyploidization was hindered.
1. The western blotting method detects the expression of CD41a/CD62P in each group of cells.
The western blotting method detects the expression of CD41a/CD62P in each group of cells. The results showed that the expression of CD41a/CD62P protein was reduced after CREG knockdown, and the results are shown in FIGS. 3-5.
2. The expression of CD41a/CD62P was detected by flow cytometry.
Collecting cells on the 4 th day of PMA induced differentiation, washing with precooled PBS, adding 2ml of 70% ethanol, and fixing at 4 ℃ overnight; 20ul of mouse anti-human CD41a/CD62P antibody is added respectively, incubated for 30min at 37 ℃ in the dark, washed once by PBS and detected by a flow cytometer. The experimental results show that: megakaryocyte maturation after CREG knockdown was hindered and the results are shown in figure 2.
3. Flow cytometry detects doubling of cellular DNA.
Collecting cells on the 4 th day of PMA induced differentiation, washing with precooled PBS, adding 2ml of 70% ethanol, and fixing at 4 ℃ overnight; adding 100ul of RNase, incubating at 37 deg.C in the dark for 30min, adding PI staining solution, incubating at room temperature in the dark for 30min, and detecting with flow cytometer. The experimental results show that: DNA ploidy was hindered after CREG knockdown, and the results are shown in fig. 3-5.
Example 3 the relationship of the effect of differentiation-promoting factor C/EBP β on CREG was examined.
1. Promoter binding Transcription Factor (TF) assay array for hCREG core promoter.
Promoter binding Transcription Factor (TF) assay array assay of the hCREG core promoter is a competitive binding assay that identifies transcription factors that bind to the promoter by comparing results in the presence (control + promoter) or absence (control) of the hCREG core promoter. If the hCREG promoter contains a TF binding sequence, it will exhibit less chemiluminescent activity. As a result, it was found that hCREG could bind to C/EBP β.
2. The expression of CD41a/CD62P/CREG protein was detected upon C/EBP β knockdown using western blot.
The expression of CD41a/CD62P/CREG protein during C/EBP beta knockdown is detected by using western blot, and the result shows that the expression of CD41a/CD62P/CREG protein is obviously reduced during C/EBP beta knockdown, and the result is shown in FIGS. 6-7.
The research results show that the CREG protein is expected to become an effective medicament for treating megakaryocyte developmental maturation disorder and thrombocytopenia.
Sequence listing
<110> general hospital in north war zone of China's liberation army
Medical application of CREG protein in megakaryocyte maturation differentiation thrombocytopoiesis
<160>4
<170>PatentIn version 3.3
<210>1
<211>21
<212>RNA
<213> Artificial sequence
<400>1
GACTTTGGCA CAGACCAACT T 21
<210>2
<211>22
<212>RNA
<213> Artificial sequence
<400>2
CAGGGTGTCG AATGAATAAC GA 22
<210>3
<211>21
<212>RNA
<213> Artificial sequence
<400>3
GGAGCGAGAT CCCTCCAAAA T 21
<210>4
<211>23
<212>RNA
<213> Artificial sequence
<400>4
GGCTGTTGTC ATACTTCTCA TGG 23
Claims (10)
1. Use of a CREG protein or an active fragment thereof for the preparation of a medicament for the prevention and/or treatment of a hematological disorder.
2. The use according to claim 1, wherein the hematological disorder is megakaryocyte maturation disorder, thrombocytopenic disease including ITP, MDS and acute megakaryocytic leukemia.
Use of CREG protein or active fragments thereof in the manufacture of a medicament or inducer for the in vitro artificial culture of platelet production.
4. Use of a recombinant vector or recombinant cell expressing a CREG protein in the manufacture of a medicament for the prevention and/or treatment of hematological disorders, wherein said recombinant cell comprises a recombinant vector expressing a CREG protein or an active fragment thereof, said recombinant vector comprising a nucleotide sequence encoding a CREG protein or an active fragment thereof.
5. The use according to claim 4, wherein the recombinant vector is a recombinant adenoviral vector.
6. Use of an agent capable of inhibiting the down-regulation of CREG protein expression or an active fragment thereof, or an agent that promotes the up-regulation of CREG protein expression or an active fragment thereof, in the manufacture of a medicament for the prevention and/or treatment of a hematological disorder.
7. The use of CREG protein or active fragments thereof for screening drugs for preventing and/or treating hematological diseases.
8. Use of an agent for detecting the expression level of a CREG protein or an active fragment thereof for the preparation of a kit for the diagnosis of a disease in the blood system.
9. A composition comprising a CREG protein or an active fragment thereof, a recombinant vector or a recombinant cell expressing a CREG protein or an active fragment thereof, or an agent capable of inhibiting the down-regulation of the expression of a CREG protein or an active fragment thereof or an agent promoting the up-regulation of the expression of a CREG protein or an active fragment thereof, and optionally a pharmaceutically acceptable carrier or excipient.
10. Use of a composition according to claim 9 for the preparation of a medicament for the prevention and/or treatment of a disease of the blood system.
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| US20150232522A1 (en) * | 2012-08-17 | 2015-08-20 | Chubu University Educational Foundation | Brown adipocyte differentiation-inducing agent |
| CN105194651A (en) * | 2015-07-30 | 2015-12-30 | 中国人民解放军沈阳军区总医院 | Medical application of CREG protein to myocardial Ischemia-reperfusion injury protection |
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| CN105194651A (en) * | 2015-07-30 | 2015-12-30 | 中国人民解放军沈阳军区总医院 | Medical application of CREG protein to myocardial Ischemia-reperfusion injury protection |
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| CN112915196A (en) * | 2021-03-15 | 2021-06-08 | 中国人民解放军北部战区总医院 | Medical application of CREG1 protein in preventing or treating sorafenib-induced myocardial injury |
| CN112915196B (en) * | 2021-03-15 | 2024-01-09 | 中国人民解放军北部战区总医院 | Medical application of CREG1 protein in preventing or treating sorafenib-induced myocardial injury |
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