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CN118127010A - SiRNA molecule for inhibiting ATF6 alpha gene and application thereof - Google Patents

SiRNA molecule for inhibiting ATF6 alpha gene and application thereof Download PDF

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Publication number
CN118127010A
CN118127010A CN202410167890.9A CN202410167890A CN118127010A CN 118127010 A CN118127010 A CN 118127010A CN 202410167890 A CN202410167890 A CN 202410167890A CN 118127010 A CN118127010 A CN 118127010A
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sirna molecule
seq
rna single
sirna
gene
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Inventor
姚婕
严国智
刘梓键
李志豪
卢展涛
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Foshan City Nanhai District People's Hospital
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Foshan City Nanhai District People's Hospital
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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Abstract

The invention relates to the technical field of biology, and discloses an siRNA molecule for inhibiting ATF6 alpha gene and application thereof. The siRNA molecule is any one of the following (1) to (3); (1) SEQ ID NO:1 and the RNA single strand shown in SEQ ID NO:2, the siRNA molecule is formed by complementation of RNA single chains; (2) SEQ ID NO:3 and the RNA single strand shown in SEQ ID NO:4, the siRNA molecules are formed by complementary RNA single strands; (3) SEQ ID NO:5 and the RNA single strand shown in SEQ ID NO:6, and the RNA single strand is complementary to the siRNA molecule. The siRNA molecule can inhibit the expression of ATF6 alpha gene and inhibit the expression of Th17 cell differentiation gene, so that the proportion of Th17 cells can be reduced, and a brand new target point is provided for treating RA.

Description

SiRNA molecule for inhibiting ATF6 alpha gene and application thereof
Technical Field
The invention relates to the technical field of biology, in particular to an siRNA molecule for inhibiting ATF6 alpha gene and application thereof.
Background
Rheumatoid Arthritis (RA) is a chronic systemic inflammatory disease, the most common systemic autoimmune disease. The pathogenesis of RA is very complex and is related to many factors such as genetics, immunity and the like, but it cannot be elucidated at present. RA is closely related to the sustained presence of an inflammatory response in the body, which activates ER stress, and thus expression of Th17 cells that secrete inflammatory factors and ER stress-related proteins is of great interest. Meanwhile, in previous studies, it was found that macrophage Migration Inhibitory Factor (MIF) plays an important role as a cytokine in autoimmune diseases, and can promote secretion of inflammatory factors.
In combination with the above, the previous results, after studying their role in the progression of RA, showed that ER stress was activated in CD4+ T cells of RA patients, that the proportion of Th17 was increased, that MIF and IL-17A were up-regulated and that MIF interacted with ATF6, and that the expression of proteins associated with Th17 cell differentiation was up-regulated, suggesting that MIF could induce Th17 cell differentiation by enhancing the activated ATF6 pathway.
Therefore, it is necessary to develop an siRNA molecule for inhibiting atf6α gene and its application, so as to effectively inhibit expression of atf6α gene, reduce expression of Th17 cell differentiation gene, and down regulate Th17 cell proportion, and provide a new target for RA treatment.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides an siRNA molecule for inhibiting ATF6 alpha gene and application thereof, thereby effectively inhibiting the expression of ATF6 alpha gene, simultaneously reducing the expression of Th17 cell differentiation gene, and down regulating the proportion of Th17 cells, and providing a brand new target point for treating RA.
In a first aspect, the invention provides an siRNA molecule that inhibits the atf6α gene.
Specifically, the siRNA molecule is any one of the following (1) to (3);
(1) SEQ ID NO:1 and the RNA single strand shown in SEQ ID NO:2, the siRNA molecule is formed by complementation of RNA single chains;
(2) SEQ ID NO:3 and the RNA single strand shown in SEQ ID NO:4, the siRNA molecules are formed by complementary RNA single strands;
(3) SEQ ID NO:5 and the RNA single strand shown in SEQ ID NO:6, and the RNA single strand is complementary to the siRNA molecule.
In a second aspect the invention provides a DNA molecule capable of producing an siRNA molecule of the first aspect.
In a third aspect of the invention, a kit is provided.
In particular, the kit comprises the siRNA molecule of the first aspect or the DNA molecule of the second aspect.
In a fourth aspect, the present invention provides the use of an siRNA molecule in the manufacture of a medicament for the prevention and/or treatment of inflammation.
Preferably, the inflammation comprises joint inflammation.
Further preferably, the joint inflammation comprises rheumatoid arthritis.
In a fifth aspect, the invention provides the use of an siRNA molecule for the preparation of a medicament for protecting cartilage and/or synovium.
The sixth aspect of the invention provides an application of an siRNA molecule in preparing a drug for inhibiting ATF6 alpha gene expression.
The seventh aspect of the invention provides an application of an siRNA molecule in preparing a drug for inhibiting expression of Th17 cell differentiation genes.
In an eighth aspect, the present invention provides an application of an siRNA molecule in preparing a medicament for reducing a Th17 cell proportion induced by a macrophage migration inhibitory factor.
Compared with the prior art, the invention has the following beneficial effects:
The siRNA molecule can inhibit the expression of ATF6 alpha gene, inhibit ATF6 alpha channel and inhibit the expression of Th17 cell differentiation gene, so that the proportion of Th17 cells can be reduced, the differentiation of Th17 cells of RA patients can be inhibited, and the siRNA molecule can be applied to preparing medicines for preventing and/or treating rheumatoid arthritis, thereby providing a brand new target point for treating RA.
Drawings
FIG. 1 is a graph showing the results of expression of MIF and ATF 6. Alpha. Genes in HC and RA groups;
FIG. 2 is a graph showing the expression results of IL-17A in the presence of Th17 cells in HC and RA groups;
FIG. 3 is a graph showing the results of expression of differentiation genes of Th17 cells in HC and RA groups;
FIG. 4 is a graph showing the results of MIF expression of ATF 6. Alpha. Gene after rhMIF stimulation with RA group;
FIG. 5 is a graph showing the effect of siRNA molecules of example 1 on ATF6 alpha gene and Th17 cell differentiation gene expression;
FIG. 6 is a graph showing the effect of siRNA molecules of example 1 on Th17 cell differentiation.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples will be presented. It should be noted that the following examples do not limit the scope of the invention.
The starting materials, reagents or apparatus used in the following examples are all available from conventional commercial sources or may be obtained by methods known in the art unless otherwise specified.
Example 1
An siRNA molecule for inhibiting ATF6 alpha gene.
TABLE 1 Single stranded sequence of siRNA molecules
Sequence name Sequence (5 'to 3')
SEQ ID NO：1 GUGAGCUACAAGUGUAUUATT
SEQ ID NO：2 UAAUACACUUGUAGCUCACTT
Example 2
An siRNA molecule for inhibiting ATF6 alpha gene.
TABLE 2 Single stranded sequence of siRNA molecules
Sequence name Sequence (5 'to 3')
SEQ ID NO：3 GCACCAUCCCUGAGUCAUUTT
SEQ ID NO：4 AAUGACUCAGGGAUGGUGCTT
Example 3
An siRNA molecule for inhibiting ATF6 alpha gene.
TABLE 3 Single stranded sequence of siRNA molecules
Sequence name Sequence (5 'to 3')
SEQ ID NO：5 GGAGACAGCAACGUAUGAUTT
SEQ ID NO：6 AUCAUACGUUGCUGUCUCCTT
Example 4
Cd4+ T cells were collected for RA and HC groups.
Experimental grouping:
RA group:
rheumatoid arthritis incorporates criteria:
1) Patient clinical data are complete and positive for rheumatoid factor and anti-cyclic guanidine amino acid polypeptide antibodies;
2) Patient conditions met the classification criteria of the american college of rheumatology.
Exclusion criteria:
Patients with other autoimmune diseases; infection is present in recent years, and other diseases (such as tumor and infectious disease) are treated.
HC group:
Healthy control group inclusion criteria:
1) No autoantibody negative and no clinical symptoms of rheumatoid arthritis;
2) No infection, tumor and other autoimmune diseases;
No history of significant disease has been found for 2 years.
The experimental steps are as follows:
1. Extraction of peripheral blood mononuclear cells PBMC
1. Respectively taking 3mL Ficoll lymphocyte separating liquids of an RA group and an HC group, placing the separating liquids into a 15mL sterile enzyme-free centrifuge tube, slowly dripping 5mL heparin anticoagulated whole blood along the tube wall onto the liquid surface of the separating liquid, placing the separating liquid into a low-speed centrifuge, and centrifuging at the room temperature for 20min at the speed of 450 Xg;
2. taking a 15mL centrifuge tube, adding 3mL PBS buffer, carefully sucking the PBMC layer (in the middle of the plasma layer and the Ficoll lymph separation liquid layer, in the form of cloud suspension and in the lowest layer, in the form of red blood cell layer) into the PBS buffer after sucking the plasma, and centrifuging for 10min at 450 Xg;
3. Removing supernatant, adding 2mL of erythrocyte lysate, re-suspending, performing room temperature lysis for 10min, and centrifuging for 10min at 450 Xg;
4. The supernatant was discarded, washed twice more with PBS buffer, and centrifuged at 450 Xg for 5min;
5. after centrifugation, the supernatant was discarded and the collected PBMCs were used as such or frozen at-80 ℃.
2. Magnetic bead sorting of CD4+ T cells
1. The PBMC cells of the RA group and the HC group were collected in a flow tube, washed twice with PBS containing 3% FBS (hereinafter abbreviated as PBS), centrifuged at 450 Xg for 5min, and the cell numbers were counted;
2. resuspension cells with 250 μl PBS, adding appropriate amount of cell antibodies according to the ratio of the instructions, vortex mixing, incubating for 5min at room temperature;
3. vortex mixing magnetic beads, adding magnetic beads according to the proportion of 1:1 antibody magnetic beads, adding PBS to 2.5mL, mixing uniformly, placing in a magnet, and incubating for 3min at room temperature;
4. the liquid in the tube was poured back and CD4+ T cells from both RA and HC groups were collected, respectively.
Example 5
The expression of MIF and ATF 6. Alpha. Genes was examined.
RNA and protein from CD4+ T cells from the RA and HC groups of example 4 were extracted and detected using RT-PCR and Western blot, respectively.
As can be seen from FIG. 1, the MIF and ATF6α expression was increased at both mRNA and protein levels in the RA group compared to the HC group.
Example 6
The Th17 cell proportion and serum IL-17A expression were examined.
PBMC from the RA group and the HC group of example 4 were separated by density gradient centrifugation, and each group of PBMC was stimulated with the cell stimulating mixture for 6 hours, and a flow test was performed to observe the change of Th17 cells; ELISA kit for measuring serum IL-17A expression.
As can be seen from fig. 2, the proportion of Th17 cells in the RA group was increased compared to the HC group; the expression of IL-17A was elevated in the serum of the RA group.
Example 7
And detecting the expression condition of the Th17 cell differentiation gene.
RNA and protein of CD4+ T cells of RA group and HC group of example 4 were extracted, respectively, and differentiation gene expression of Th17 cells was detected using RT-PCR and Western blot, respectively.
As can be seen from FIG. 3, the expression of the differentiation genes STAT3 and RORC associated with the RA group Th17 cells was increased compared to the HC group.
Example 8
The effect of MIF on ATF6 alpha gene expression was examined.
The CD4+ T cells of the RA group of example 4 were collected, one group was stimulated for 6 hours by adding rhMIF, and the other group was not stimulated by adding rhMIF, and each group was extracted for protein detection.
As can be seen from FIG. 4, the WesternBlot results show that MIF can increase the expression of ATF6α, i.e. MIF enhances ER stress in RA patients, and ATFα expression is increased.
Example 9
The effect of siRNA molecules of example 1 on the expression of ATF 6. Alpha. Gene and Th17 cell differentiation gene was examined.
Example 4RA sets of cd4+ T cells were collected, one of which was transfected with the siRNA molecule of example 1, and the protein lysate was extracted by adding rhMIF to stimulate for 6 h. Another group was transfected with CD4+ T cells without using the siRNA molecule of example 1, and protein lysates were extracted by adding rhMIF for 6h stimulation.
Specific steps of siRNA transfection of CD4+ T cells:
1. on the day of cell transfection, cells were collected in centrifuge tubes, resuspended in serum-containing medium, and the cell numbers were counted. The number of cells in 400. Mu.L of medium per well was 1X 10 6 calculated on a 24-well plate.
2. Transfection:
At 100uL 55Pmoles of the siRNA of example 1 was added and vortexed slowly for 10s; addition of/>Slowly vortex the reagent for 1s, and standing at room temperature for 10min; and then the mixed solution is evenly added into a 24-hole plate, and the mixture is cultivated for 48 hours in a incubator.
And (3) after observing fluorescence for 3.48 hours, collecting samples, and finishing transfection.
From FIG. 5, it can be seen from the WesternBlot results that the siRNA molecule of example 1 effectively inhibited the expression of ATF 6. Alpha. Gene and simultaneously inhibited the expression of Th17 cell differentiation gene.
Example 10
The effect of the siRNA molecules of example 1 on Th17 cell differentiation was examined.
After collection of the PBMCs of the RA group of example 4, one group was transfected with the siRNA molecules of example 1 while adding rhMIF to stimulate for 3d, a flow-through experiment was performed. Another group was subjected to flow-through experiments without transfecting PBMCs with the siRNA molecule of example 1, with the addition of rhMIF for 3d stimulation only. The procedure for transfection of PBMC with siRNA molecules was as described in example 9.
From FIG. 6, it is understood from the flow results and statistics that the siRNA molecules of example 1 can reduce the proportion of Th17 cells induced by MIF, i.e., the siRNA molecules of the present invention can inhibit differentiation of Th17 cells in RA patients.
In conclusion, the results of the invention show that the siRNA molecule prepared by the invention can inhibit the expression of ATF6 alpha gene, inhibit ATF6 alpha channel and inhibit the expression of Th17 cell differentiation gene, thereby reducing the proportion of Th17 cells, inhibiting the differentiation of Th17 cells of RA patients and further being applied to the preparation of medicaments for preventing and/or treating rheumatoid arthritis.
The foregoing describes in detail preferred embodiments of the present invention. It should be understood that numerous modifications and variations can be made in accordance with the concepts of the invention by one of ordinary skill in the art without undue burden. Therefore, any modification, equivalent replacement, improvement or the like of the prior art through logic analysis, reasoning or limited experiments according to the present invention will be within the scope of protection defined by the claims.

Claims (10)

1. An siRNA molecule that inhibits the atf6α gene, characterized in that the siRNA molecule is any one of the following (1) to (3);
(1) SEQ ID NO:1 and the RNA single strand shown in SEQ ID NO:2, the siRNA molecule is formed by complementation of RNA single chains;
(2) SEQ ID NO:3 and the RNA single strand shown in SEQ ID NO:4, the siRNA molecules are formed by complementary RNA single strands;
(3) SEQ ID NO:5 and the RNA single strand shown in SEQ ID NO:6, and the RNA single strand is complementary to the siRNA molecule.
2. A DNA molecule capable of producing the siRNA molecule of claim 1.
3. A kit comprising the siRNA molecule of claim 1 or the DNA molecule of claim 2.
4. Use of the siRNA molecule of claim 1 for the preparation of a medicament for the prevention and/or treatment of inflammation.
5. The use of claim 4, wherein the inflammation comprises joint inflammation.
6. The use according to claim 5, wherein the joint inflammation comprises rheumatoid arthritis.
7. Use of the siRNA molecule of claim 1 for the preparation of a medicament for protecting cartilage and/or synovium.
8. Use of the siRNA molecule of claim 1 for the preparation of a medicament for inhibiting expression of atf6α gene.
9. Use of the siRNA molecule of claim 1 for the preparation of a medicament for inhibiting expression of a Th17 cell differentiation gene.
10. Use of the siRNA molecule of claim 1 for the manufacture of a medicament for reducing the Th17 cell fraction induced by macrophage migration inhibitory factor.
CN202410167890.9A 2024-02-06 2024-02-06 SiRNA molecule for inhibiting ATF6 alpha gene and application thereof Pending CN118127010A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080194419A1 (en) * 2005-05-23 2008-08-14 Universiteti Maastricht Genetic Association of Polymorphisms in the Atf6-Alpha Gene with Insulin Resistance Phenotypes
US20100266618A1 (en) * 2009-03-18 2010-10-21 Children's Hospital Of Eastern Ontario Research Institute Compositions and methods for augmenting activity of oncolytic viruses
CN115135645A (en) * 2019-10-09 2022-09-30 普拉西斯生物技术有限责任公司 ATF6 modulators and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080194419A1 (en) * 2005-05-23 2008-08-14 Universiteti Maastricht Genetic Association of Polymorphisms in the Atf6-Alpha Gene with Insulin Resistance Phenotypes
US20100266618A1 (en) * 2009-03-18 2010-10-21 Children's Hospital Of Eastern Ontario Research Institute Compositions and methods for augmenting activity of oncolytic viruses
CN115135645A (en) * 2019-10-09 2022-09-30 普拉西斯生物技术有限责任公司 ATF6 modulators and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DANDAN WU等: "Unfolded protein response factor ATF6 augments T helper cell responses and promotes mixed granulocytic airway inflammation", 《MUCOSAL IMMUNOL.》, vol. 16, no. 4, 19 May 2023 (2023-05-19), pages 499 *
张朋威等: "内质网应激在膝骨关节炎进程中的作用研究进展", 《中国组织化学与细胞化学杂志》, vol. 32, no. 6, 20 December 2023 (2023-12-20), pages 636 - 641 *
狄明雪: "ox-LDL调节内皮细胞DKK1的分子机制及对动脉粥样硬化发生发展的影响", 《中国博士学位论文全文数据库（电子期刊）医药卫生科技辑》, 15 January 2021 (2021-01-15), pages 062 - 91 *
马炜祥: "内质网应激关键分子ATF6α在肝细胞癌发展中的作用", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》, 15 January 2023 (2023-01-15), pages 072 - 1297 *

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