CN104436195B - Purposes of the miR-155 in preparation prevention and treatment acute lung injury drug - Google Patents
Purposes of the miR-155 in preparation prevention and treatment acute lung injury drug Download PDFInfo
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Abstract
The present invention relates to purposes of the miR-155 in preparation prevention and treatment acute lung injury drug.The invention firstly discloses miR-155 and acute lung injury, there are Close relations, promote the generation of acute lung injury.Therefore, the lower adjustment of the miR-155 can be used for preventing, alleviate or treat acute lung injury, especially acute empsyxis.
Description
Technical field
The invention belongs to biomedicine fields；More particularly it relates to which miR-155 prevents and treats acute lung injury in preparation
Purposes in drug.
Background technique
Empsyxis is a serious complication of systemic loupus erythematosus (SLE), although its disease incidence is very low (1.9%),
But its death rate very high (92%) [1].Although many case reports report a series of diseases for suffering from Diffuse Pulmonary Hemorrhage (DAH)
People, but its pathogenesis is still unknown.Secondly, empsyxis is often with inflammatory cell infiltration, immune complex deposit etc. other
Change.Documents and materials report hinders people to SLE complication lung with empsyxis immunopathogenesis and the inconsistency of clinical manifestation
Pathogenetic research of bleeding.The most information of histogenic immunity pathology is obtained by necropsy, so can not continuously analyze
The mechanism of empsyxis.
Norphytane (Pristine；2,6,10,14-tetramethylpentadecane) lupus mouse model is exactly induction type
One kind of mouse model can generate lupus specific antibody after 0.5ml norphytane is injected intraperitoneally in non-self immunized mice
(anti-su, anti-Sm, anti-Rib P, Anti-hCG action), lupus correlation antibody (anti-ssDNA, anti-nRNP, histonic antibody) lung
Portion's lesion and immune-complex type glomerulonephritis etc. [2].There is study group's discovery recently, there are about 50% in one month after injection
C57 mouse die of empsyxis, macroscopic empsyxis can be shown within 2 weeks after injection, and this bleeding is likely to and B cell
Hyperfunction correlation [3,4].This provides a good disease model to study the pathogenesis of empsyxis.
Microrna (microRNA, miRNA) be a kind of length of endogenous expression generally existing in animal and plant body about
The single-stranded microRNA of non-coding protein of 21-25nt, is integrated on specific said target mrna by nucleic acid array complementation and is adjusted
Save said target mrna translation or degradation said target mrna, be it is a kind of serve transcription after negative regulation molecule, participation life process in a system
Important process is arranged, various biological effect is played.MiRNAs is an important breakthrough of scientific research in recent years.Numerous research tables
Bright miRNA takes part in the links of immune system effect, including the reaction of inherent immunity, adaptive immunity, immunocyte
Development etc., carries out fine adjusting [5,6] to immune system.Some miRNA having differences property table in normal person and SLE patient
It reaches and related to lupus morbidity [7,8].It is lowered as SLE peripheral blood in patients miRNA-146a is expressed, weakens I type interferon access
Negative tune act on [9].MiRNA-125a expresses defect, leads to the secretion of the inflammatory chemotactic factor (CF) RANTES of lupus patient T cell
Increase [10].MiRNA-21 and miRNA-148 is by directly or indirectly inhibiting DNA first in lupus patient peripheral blood CD4+ cell
Base transferase I, and then promote the expression [11] of the autoimmunity related gene of some methyl-sensitives.
MiRNA is suffered from important as a kind of important regulatory molecule in the occurrence and development process of a variety of diseases of the mankind
Effect.It is different from the past with or without adjusting feature, miRNA is mainly quantitatively adjusted target gene.This is special
Point is that the antagonist and agonist of the powerful adjustment effect of the mono- target spot of siRNA or some molecules are incomparable.This present
Huge prospect of the miRNA in terms of clinical application.In view of in animal body there are diversified miRNA, and known many miRNA
With disease there are close relationship, this field also need further explore miRNA effect, to clinically play prevention or
Therapeutic effect.
Summary of the invention
The purpose of the present invention is to provide purposes of the miR-155 in preparation prevention and treatment lupus acute lung injury drug.
In the first aspect of the present invention, the purposes adjusted under a kind of miR-155 is provided, prevention and treatment acute lung injury is used to prepare
Composition.
In a preferred embodiment, the dosage form injury of lungs is empsyxis.
In another preferred example, the composition is also used to: lowering the water of inflammatory factor in dosage form injury of lungs subject
It is flat.
In another preferred example, the inflammatory factor includes: IL-1b, IL-6, TNF-a or IL-17.
In another preferred example, adjust under the miR-155 is to inhibit or prevent miR-155 and its target gene site
In conjunction with substance.
In another preferred example, under the miR-155 adjust include: miR-155 antagonist (Antagomir),
The antisense nucleic acid of miR-155, the lock nucleic acid antisense nucleic acid of miR-155；Or carry or express the antisense nucleic acid of miR-155, miR-
The construction of 155 lock nucleic acid antisense nucleic acid.
In another preferred example, adjusting under the miR-155 is: miR-155 antagonist shown in SEQ ID NO:2.
In another preferred example, in sequence shown in SEQ ID NO:2,3 ' ends carry out cholesterol label, 5 ' end 2, end alkali
Base is modified plus thiophosphoric acid site, and 3 ' end 4, end bases are modified plus thiophosphoric acid site, complete 2 '-methylation of chain modification.
In another aspect of this invention, it provides and is adjusted under a kind of miR-155, be miR-155 shown in SEQ ID NO:2
Antagonist.
In a preferred embodiment, in sequence shown in SEQ ID NO:2,3 ' ends carry out cholesterol label, 5 ' end 2, end alkali
Base is modified plus thiophosphoric acid site, and 3 ' end 4, end bases are modified plus thiophosphoric acid site, complete 2 '-methylation of chain modification.
Other aspects of the invention are apparent to those skilled in the art due to this disclosure
's.
Detailed description of the invention
The grouping of intervention experiment in Fig. 1, miR-155 body.
Fig. 2, miR-155 knock-out mice have repellence to the Pristane empsyxis induced.A is normal C57 mouse in abdomen
Chamber injects the photo of 14 days lungs of Pristane/PBS；B is 14 day lungs of the normal C57 mouse in intraperitoneal injection Pristane/PBS
The expression of middle miR-155；C is the paraffin section of lung, H&E dyeing；B is the system of the injury of lungs percentage of Pristane induction
Meter.ALD:acute lung damage.NON ALD: without ALD.
Fig. 3, living body intervene the generation that miR-155 can prevent the empsyxis of Pristane induction.A is that the paraffin of lung is cut
Piece, H&E dyeing.MiR-155anta:miR-155antagomir；NC: negative control (negative control).B is
The statistics of the injury of lungs percentage of Pristane induction.C is the quantitative result of miR-155.Pri:pristine.
Fig. 4, miR-155 can promote the secretion of inflammatory factor in serum.
A kind of structural schematic diagram of Fig. 5, miR-155 antagomir.
Specific embodiment
The present inventor is by long-term research, it has unexpectedly been found that there are Close relations with acute lung injury by miR-155.Base
It can be used for lowering miR-155 in the lower adjustment of announcement of the invention, the miR-155, to prevent, alleviate or treat and is acute
Injury of lungs, especially acute empsyxis.
MiR-155 and application thereof
In the present invention, the miR-155 is the micro ribonucleic acid with nucleic acid sequence shown in SEQ ID NO:1:
5 '-UUAAUGCUAAUUGUGAUAGGGGU-3 ' (SEQ ID NO:1)
MiR-155 is a kind of microRNA (miRNA) small molecule known in the art, is useful for rna regulation.
MiR-155 is encoded by Bic (B cell integration cluster) gene.Discovery is in many B cell lymphs earliest
In cancer, Bic/miR-155 expression is very high.And also there is precursor B cells paraplasm in the miR-155 mouse of transgenosis
Phenotype [15].In addition, the up-regulation of miR-155 is also observed in the B cell and T cell and dendritic cells of normal Activate,
This illustrates that miR-155 also plays an important role [16] in normal immunological response.
MiR-155 can induce [17] by stimulations such as TLR ligand, interferon and TNF αs.By targeting PU.1, miR-
155 take part in B cell maturation, the adjusting [18] of immunoglobulin class conversion.MiR-155 can be by targeting SOCS1, regulation
The differentiation of Treg, to function [19] in EAE disease.MiR-155 can also be answered by being directly targeted SHIP in inflammation
It answers and play a role in tumour [20].In addition, the BCR on normal B cells surface can promote the expression [21] of miRNA-155.
The growth of the mouse lymphocyte of miRNA-155 gene knockout is normal but the immunodeficiency of B cell, thick liquid cell quantity subtract
It is few, the decline of IgG quantity and hypofunction [22].
However, not known at present for the miR-155 target spot combined and its correlation between acute lung injury.This
Wen Zhong, the acute lung injury include empsyxis, but the diseases such as pulmonary fibrosis are not belonging to the scope of acute lung injury.
MiR-155 can be isolated from cell, or can be obtained by artificial synthesized mode.Knowing miR-155
Or after the sequence of its precursor, those skilled in the art prepare miR-155 or its precursor in which can be convenient.
The present inventor utilizes the mouse of miR-155 gene knockout, detects its reaction for empsyxis.And combine living body
The artificial synthesized inhibitor antagomir tail vein injection of miR-155 is entered in mouse, observes it and lung is gone out by intervention experiment
The influence of the induction of blood.By the tissue section strain of H & E, pathological analysis is carried out to mouse.It is detected by RT-qPCR
Inhibition efficiency of the antagomir to miR-155.Cytokine of Serum is detected by Bioplex cell factor suspending chip
Variation.As a result, it has been found that the C57 mouse of miR-155 gene knockout has repellence to empsyxis.In living body intervention experiment, injection
The mouse of miR-155antagomir has 80% will not fall ill, and the mouse of normal Pristane induction has 80% morbidity.RT-
QPCR is the results show that the mouse in injection miR-155antagomir respectively organizes the miR-155 expression of internal organs all to be lowered.
Bioplex the result shows that, some inflammatory factors, such as IL-1b, IL-6, TNF-a, IL17, Pristane induction 14 days just
It is significantly raised in normal mouse, and in miR-155KO mouse, the expression of these factors is all very low.Therefore, exist
In the empsyxis of Pristane induction, miR-155 plays positive effect.By gene knockout miR-155, or inject its suppression
Preparation can reduce significantly the expression of some inflammatory factors in serum, to reduce the disease incidence of empsyxis.Cause
This, miR-155 is the new drug target of an acute lung injury therapeutic intervention.
MiR-155 is the drug screening of target spot
After knowing the Close relation of miR-155 and acute lung injury, inhibition can be screened based on this feature
The substance of miR-155.Later, the drug actually useful for acute lung injury can be found from the substance.
Therefore, the present invention provides a kind of method of potential substance for screening acute lung injury, and the method includes: with time
Select the system of substance processing expression miR-155；With the expression or activity for detecting miR-155 in the system；If the candidate
Matter can inhibit the expression or activity of miR-155, then shows that the candidate substances are the potential substances of acute lung injury.The expression
The system of miR-155 for example can be cell (or cell culture) system, and the cell can be endogenous expression miR-
155 cell；Or it can be the cell of recombinant expression miR-155.The system of the expression miR-155 can also be subcellular
System, solution system, organizational framework, organ systems or animal system (such as animal model, preferably the animal mould of non-human mammal
Type, such as mouse, rabbit, sheep, monkey) etc..
In a preferred embodiment of the present invention, when being screened, in order to be more easily observable the expression or activity of miR-155
Change, also settable control group, the control group can be do not add the candidate substances expression miR-155 body
System.
As preferred embodiment of the invention, the method further include: the potential substance of acquisition is carried out further thin
Born of the same parents' experiment and/or animal experiment, further to select and determine the substance actually useful for acute lung injury.
On the other hand, the present invention also provides the potential substances of the acute lung injury obtained using the screening technique.This
The substance that a little preliminary screenings go out may make up a screening library, in order to people may finally be screened out from it can be for inhibition
The expression and activity of miR-155, and then the substance that acute lung injury is useful.
MiR-155 regulator and application thereof
Above-mentioned new discovery based on the present inventor, the present invention provides the purposes adjusted under a kind of miR-155, are used to prepare
Inhibit the composition of acute lung injury
As used herein, " the adjusting under miR-155 " includes nucleic acid inhibitor, antagonist, inhibitor, retardance
Agent, blocking agent etc., as long as they can lower miR-155 or the expression of its precursor.It is small that they can be compound, chemistry
Molecule, biomolecule.The biomolecule can be nucleic acid level (including DNA, RNA), be also possible to protein level.
Under the miR-155 adjust refer to it is any prevent miR-155 (combination critical sites especially therein) or
Its precursor with its target sequence in conjunction with, the activity that reduces miR-155 or its precursor, the stability for reducing miR-155 or its precursor,
It lowers the expression of miR-155 or its precursor, reduce miR-155 or the substance of its precursor effective acting time, these substances
, so as to be used to inhibit acute lung injury, more particularly press down for the present invention as lowering the useful substance of miR-155
Empsyxis processed.For example, the lower adjustment is: nucleic acid inhibitor, protein inhibitor, antibody, ligand, nuclease, nucleic acid combine
Molecule, as long as its expression that can lower miR-155.
As a kind of mode of the invention, the lower adjustment is nucleic acid inhibitor.Preferably, the nucleic acid inhibitor
In conjunction with preventing miR-155 from targeting sequence with it, to play a role.The nucleic acid inhibitor is for example selected from (but unlimited
In): the antisense nucleic acid of miR-155, the lock nucleic acid antisense nucleic acid of miR-155；Peptide nucleic acid；SiRNA (silencing miR-155 precursor).
As preferred embodiment of the invention, the lower adjustment of the miR-155 is miR-155antagomir.
The length of Antagomir generally in 22-25nt, be by special chemical modify miRNA antagonist, by with it is intracorporal at
The ripe strong competitive binding of miRNA prevents the complementary pairing of miRNA and its target gene mRNA, and miRNA is inhibited to play a role.With it is general
Logical lower adjust is compared, and miRNA antagomir is outer in animal body to have higher stability and inhibitory effect, and can overcome body
The obstacles such as inner cell film, tissue are enriched in target cell.Antagomir does not need transfection reagent in cell experiment, avoids transfecting
The complex steps of reagent packaging process and its influence to experiment.It can be carried out with whole body or the methods of locally injecting, sucking, medicine feed
Administration.The inventors discovered that miR-155 antagomir of the invention is especially excellent for the control efficiency of acute lung injury
's.
In the present invention, miR-155 antagomir is the single stranded RNA by special marking and modification, dedicated for inhibiting
The efficient blocking agent of endogenous microRNA.Preferably, its 3 ' ends carry out cholesterol (cholesterol) label, 5 ' ends add
The modification of upper two thiophosphoric acids site (PS), 3 ' the four thiophosphoric acid site (PS) modifications, complete 2 '-methylation of chain modification.Structure
Schematic diagram such as Fig. 5.
As another optional way of the invention, the lower adjustment of the miR-155 is the antisense nucleic acid of miR-155.
As used herein, " antisense nucleic acid " is also known as " antisense nucleic acid " or " antisense oligonucleotides (AS-ONs, antisense-
Oligonucleotides) " or " antisense drug ", refer to length be about the DNA molecular of 15-30 base, RNA molecule they
Modified form or their analog, can be complementary with mRNA.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part such as J. Pehanorm Brooker etc. is write, Molecular Cloning:A Laboratory guide, the third edition, Science Press, condition described in 2002, or
According to the normal condition proposed by manufacturer.
I. materials and methods
1, miR-155antagomir and antagomir negative control is synthesized by Ribo biotech firm.
The sequence of miR-155antagomir and antagomir negative control is as follows:
MiR-155antagomir:
5’mA(s)mC(s)mCmCmCmUmAmUmCmAmCmAmAmUmUmAmGmCmAmU(s)mU(s)mA(s)mA(s)-/
Chol/3 ' (the sequence such as SEQ ID NO:2 in non-modified situation)；
Negative control:
5’mC(s)mA(s)mGmUmAmCmUmUmUmUmGmUmGmUmAmGmUmAmC(s)mA(s)mA(s)mA(s)-
Chol3 ' (the sequence such as SEQ ID NO:3 in non-modified situation).
2, experimental animal and method
2.1 experimental animal
C57/B6 mouse (Female) is purchased from Shanghai Slac Experimental Animal Co., Ltd., the miR-155 of C57 background
Knock out mice is purchased from U.S. Jaxson lab.All mouse are all placed on Shanghai medical college, Fudan University animal experimental center SPF
Grade environment raising.
The preparation and sampling of the empsyxis animal model of 2.2Pristane induction
The Pristane of 0.5ml is disposably injected in the abdominal cavity C57/B6, induces lupus.Eyeball takes blood, peritoneal lavage after two weeks
Mouse is put to death after collecting irrigating solution.
Intervention experiment in 2.3miR-155 body
Experiment is divided into three groups, concrete operations such as Fig. 1.
Eyeball puts to death mouse after taking blood after two weeks, collects important internal organs --- liver, lung, kidney, spleen.Every kind of internal organs are divided into two
Part, portion, which is stored in formaldehyde, is used as pathological analysis, and portion deposits in -80 DEG C of refrigerators, analyzes to subsequent experimental.
3, the pathological analysis of lung
It send the lung tissue being stored in formaldehyde to the pathology department in Shanghai Second Emdical University, is made into paraffin section,
Hematoxylin & Eosin dyeing.
4, RNA extracting and reverse transcription
Trizol (Invitrogen Products) total serum IgE, obtained RNA Capillary Electrophoresis are extracted using phenol chloroform method
(NanoDrop Specthophotometer) identifies its integrality, and ultraviolet specrophotometer measures its concentration.Then, it passes through
MiRNAs specific primer reverse transcription, sample-adding system be dNTP 0.03ul, MMLV 0.2ul, 10 × Buffer 0.3ul,
RNase Inhibitor 0.02ul、ddH2O (Without RNase) 0.45ul, Primer 1ul and RNA 1ul, reverse transcription
Reaction condition is 16 DEG C of * 30min42 DEG C * 30min85 DEG C * 5min.
5, real-time fluorescence quantitative PCR (Real-time PCR)
Real-time fluorescence quantitative PCR operation is carried out in ABI Prism7900 (Applied Biosystems company).FAS
Gene SYBR Green quantitative reaction condition is 95 DEG C * 15s(95℃*5s60℃*30s) * 40 95 DEG C * 15 of circulations60℃*
15s95℃*15s。
6, BIOPLEX cell factor suspending chip
Bioplex 23 is purchased from BIO-RAD company because of cytokine suspending chip.With Bio-plex ProTM Assays
Detect the expression of cell factor in mice serum.
II. embodiment
Embodiment 1, miR-155 knock-out mice have repellence to the Pristane empsyxis induced
The present inventor has detected expression water of the miR-155 in the Mouse model of acute lung injury that Pristane is induced first
It is flat.As a result, it has been found that 0.5ml Pristane is injected intraperitoneally after two weeks, compared with the control group, expression quantity of the miR-155 in lung
Obvious up-regulation (see Fig. 2 a-b).
For the effect in clear miR-155 acute lung injury, the present inventor is carried out with the mouse of miR-155 gene knockout
The Induction experiments of Pristane.As a result, it has been found that the mouse of miR-155 gene knockout has apparent resistivity to empsyxis
(there is empsyxis in 20% mouse), and normal C57 mouse has up to 80% disease incidence (see Fig. 2 d).Compared with the control group,
MiR-155 KO mouse has complete lung mechanics (see Fig. 2 c).
Embodiment 2, living body intervene the generation that miR-155 can prevent the empsyxis of Pristane induction
In order to further clarify the effect that miR-155 is played during injury of lungs, the present inventor uses miR-155
Antagomir carries out internal intervention experiment.
The result shows that the mouse of injection miR-155antagomir (miR-155anta) goes out the Pristane lung induced
Blood has apparent resistivity (Fig. 3 a-b).
In order to verify the inhibition efficiency of miR-155 antagomir, the present inventor has collected the RNA of different tissues, does
The quantitative analysis of miR-155.As a result, it has been found that having injected the miR- that the mouse of miR-155antagomir is respectively organized at 14 days
155 expression ratio antagomir negative control groups and PBS group will be low (Fig. 3 c).This explanation, miR-155
Antagomir is that effectively, it is strictly the missing because of miR-155 that mouse, which has repellence to empsyxis,.
Embodiment 3, miR-155 can promote the secretion of inflammatory factor in serum
There is article report, miR-155 can promote some inflammatory factors, such as IL-6, TNF-a as a proinflammatory factor
Expression [14].
Therefore, in the empsyxis model that Pristane is induced, miR-155 is lacked to inflammatory factor the present inventor's detection
It generates and whether has an impact.At 14 days of Pristane induction, different groups of serum is collected, is suspended by bioplex- cell factor
Chip, the inventors discovered that, some inflammatory factors, such as IL-1b, IL-6, TNF-a, IL-17, at 14 days of Pristane induction
Normal mouse in it is significantly raised, and in miR-155KO mouse, the expression of these factors is all substantially reduced (Fig. 4).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
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Claims (3)
1. the application adjusted under a kind of miR-155 in the composition of preparation prevention and treatment systemic lupus erythematosus disease empsyxis；
Adjust under the miR-155 is miR-155 antagonist shown in SEQ ID NO:2；In sequence shown in SEQ ID NO:2,3 '
End carries out cholesterol label, and 5 ' end 2, end bases are modified plus thiophosphoric acid site, and 3 ' end 4, end bases are plus thio
The modification of phosphoric acid site, complete 2 '-methylation of chain modification.
2. application as described in claim 1, which is characterized in that the composition is also used to: it is tested to lower acute lung injury
The level of inflammatory factor in person.
3. application as claimed in claim 2, which is characterized in that the inflammatory factor includes: IL-1b, IL-6, TNF-a or
IL-17。
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| CN103025384A (en) * | 2010-03-26 | 2013-04-03 | 俄亥俄州立大学 | Materials and methods related to modulation of mismatch repair and genomic stability by mir-155 |
| CN103768601A (en) * | 2012-10-22 | 2014-05-07 | 中国科学院上海生命科学研究院 | Method for preventing and treating atherosclerosis through inhibition of micro-RNA155 |
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