CN104087678B - The application of Vinexin-β in treatment cerebral apoplexy disease - Google Patents
The application of Vinexin-β in treatment cerebral apoplexy disease Download PDFInfo
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Abstract
The present invention discloses the application of a kind of Vinexin-β in treatment cerebral apoplexy disease, belongs to function and the Application Areas of gene.The present invention with Vinexin-β knock out mice for experimental subjects, by the relation of Cell transplantation Study of damage Vinexin-β gene and cerebral apoplexy, result shows to contrast with wild type control mice, Vinexin-β knock out mice head Infarction volume obviously reduces, neural function is clearly better, and the neuronal cell quantity of head death also obviously reduces.Thus find that Vinexin-β can promote the effect of worsens neurological function and cerebral apoplexy; Therefore, Vinexin-β can be used as the medicine of drug targets screening neuroprotective function and prevention, alleviation and/or treatment cerebral apoplexy, and the inhibitor of Vinexin-β can be used for preparing the medicine of neuroprotective function and prevention, alleviation and/or treatment cerebral apoplexy.
Description
Technical field
The invention belongs to function and the Application Areas of gene, the particularly application of a kind of Vinexin-β in treatment cerebral apoplexy disease, specifically prevents in preparation, alleviates and/or treats in the medicine of cerebral apoplexy disease and apply.
Background technology
Cerebral apoplexy disease is global the fourth-largest lethal factor, is only second to cardiovascular disorder, tumour and chronic lower respiratory illness, is also one of topmost paathogenic factor causing lifelong disability.Wherein, the patient of about 80% is cerebral infarction, and principal pathogenetic reason is that cerebral blood vessel blocks or hematencephalon causes cerebral tissue blood supply for hypoxgia.It is predicted, the expense being used for Treatment of Cerebral Stroke for 2005 to the year two thousand fifty U.S. is about 1,520 hundred million dollars by purchasing power assessment in 2005, causes huge burden to economy with healthy.In China, along with Economic development, people's lives mode change and aging population, Cerebral Haemorrhage Invasion Rate raises year by year in recent years.China about has 1,600,000 people to die from cerebral apoplexy every year, and mortality ratio is 1,57/,100,000 people, has exceeded cardiovascular disorder and has become topmost lethal factor and adult's disability-causing factor.Similar to other countries, cerebral infarction is the modal stroke types of China, accounts for the 43-79% of all cerebral apoplexies.Therefore cerebral apoplexy be present and in the in the future a very long time mankind must faced by one of great public health problem.
Most research is thought, recovering cerebral tissue blood supply is the most effective means for the treatment of cerebral ischemia.Although 1996 Nian Qi tissue plasminogen activators (tPA) namely ratify to be used for cerebral infarction treatment, it remains Bureau of Drugs Supervision of the U.S. (FDA) and uniquely audits the thrombolytic drug passed through up to now.Because extend bleeding risk in time to increase, the therapeutic time window of tPA is only 4.5 hours; Consider ischemia and hemorrhagic apoplexy in early days iconography not easily differentiate, delay further patient accept tPA treatment chance.The ischemic cerebral stroke patients being only less than 5% at present uses tPA thromboembolism treatment.In addition, if research finds the long-time severe ischemic anoxic of cerebral tissue, even if recover cerebral blood flow in the later stage still can cause irreversible damage to cerebral tissue, therefore current still in the urgent need to the therapeutic strategy of research for pathophysiologic event caused by hypoxic-ischemic and (or) Reperfu-sion.
Since the nineties in 20th century, the therapeutic strategy of research neuroprotective and cerebral tissue is the focus of Treatment of Cerebral Stroke always, and these strategies not only can extend the therapeutic time window of tPA, also can alleviate the brain tissue impairment of ischemia-reperfusion induction.Neuronal cell is the important integral part of central nervous system, but its high metabolic rate reduces hypoxic-ischemic environmental resistance ability, and therefore comparatively other neural blood vessel element component are more vulnerable to damage.The treatment of current tissue plasminogen activator (tPA) fibrinolytic is still the essential therapeutic arsenals of cerebral infarction, but its only the time window of 4.5 little durations limit most of patient and can only accept symptomatic treatment.Research shows, neuro-protective strategy can improve brain function in the long period after cerebral ischemia, reduces neuronal cell loss.Apoptosis is one of fundamental mechanism of necrocytosis in cerebrum ischemia/refilling process, but its regulatory mechanism is illustrated not yet completely.Therefore, the molecular mechanism of neuronal apoptosis existence during research cerebrum ischemia/Reperfu-sion, will contribute to for neuro-protective provides new therapeutic strategy and method.
Vinexin and its associated proteins vinculin (vinculin) are the important composition compositions of the protein network of composition cell adhesion, the combination of Vinexin and vinculin directly affects the formation of adhesion plaque, and the adhesion of regulating cell-cell, cell-extracellular matrix, and finally affect a series of important cells behaviors such as the migration of cell, differentiation, division and apoptosis.Vinexin comprises 3 hypotypes, Vinexin-α, β and γ, and the albumen of these 3 kinds of hypotypes all has a SoHo(sorbinhomology at its N end) three SH3(srchomology3 of structural domain and C end) structural domain, molecular structure is high conservative all.Vinexin-β expresses in many places, especially very high at the expression level of heart.Research finds the mouse of Vinexin-β gene knockout, more responsive to the myocardial hypertrophy reaction caused by aortic coaractation operation, this shows that Vinexin-β is a very important Function protein (KeChen in the myocardial remodelling caused by high loading and reaction of exhaustion, etal.Vinexin-β protectsagainstcardiachypertrophybyblockingtheAkt-depend entsignallingpathway.BasicResCardiol, 2013,108:338).Up to the present there is no the content that bibliographical information is applied in cerebral apoplexy disease about Vinexin-β.
Summary of the invention
For solving defect and the deficiency of above-mentioned prior art; the object of the invention is to determine the mutual relationship between the expression of Vinexin-β and cerebral apoplexy disease; there is provided a kind of Vinexin-β as the application of drug targets in the medicine of screening neuroprotective function and prevention, alleviation and/or treatment cerebral apoplexy, and then the application of the inhibitor of a kind of Vinexin-β in the medicine preparing neuroprotective function and prevention, alleviation and/or treatment cerebral apoplexy is provided.
Object of the present invention is achieved through the following technical solutions:
The present invention with Vinexin-β knock out mice for experimental subjects, cerebral apoplexy model is caused by mouse brain medium sized artery ischemical reperfusion injury, the relation of research Vinexin-β gene and cerebral apoplexy, result shows compared with wild-type mice (control group), Vinexin-β knock out mice Infarction volume obviously reduces, neural function is clearly better, and dead neuronal cell quantity reduces.This points out Vinexin-β to have the effect of worsens neurological function, can increase the weight of the development promoting cerebral apoplexy, and the novel targets and the New Policy that prevent, alleviate and/or treat cerebral apoplexy disease for studying provide theoretical foundation and Clinical Basis.
Therefore, Vinexin-β gene can be used as drug target, builds In vitro cell model or the animal model of Vinexin-β gene overexpression, for screening prevention, alleviating and/or treat the medicine of cerebral apoplexy; Vinexin-β gene also can be used as the target gene in gene therapy, designs and prepares prevention, alleviates and/or the treatment medicine of cerebral apoplexy and/or biological reagent, being reached prevention by genetic engineering technique, alleviated and/or treat the object of cerebral apoplexy.Such as with Vinexin-β for target gene, design Vinexin-β can be disturbed to express double-strand siRNA, after being synthesized by chemical process, be injected into human body and make Vinexin-β gene silencing treat cerebral apoplexy by the method that RNA disturbs; Can also design and build the mutant of Vinexin-β, after injection, entering cell, the substrate specificity of competition Vinexin-β original shape, thus suppressing the function of Vinexin-β, playing therapeutic purpose; In addition, can also with Vinexin-β for shot design micromolecular compound inhibitor, utilize In vitro cell model or the animal model of Vinexin-β gene overexpression, by screening, find wherein specificity to suppress the molecule of Vinexin-β, thus provide new therapeutic molecules for the treatment of cerebral apoplexy.
For the above-mentioned functions of Vinexin-β, provide Vinexin-β as the application of drug targets in the medicine of screening neuroprotective function.
For the above-mentioned functions of Vinexin-β, provide Vinexin-β to prevent in screening as drug targets, alleviate and/or treat the application in the medicine of cerebral apoplexy.
For the above-mentioned functions of Vinexin-β, provide the application of the inhibitor of Vinexin-β in the medicine preparing neuroprotective function.
For the above-mentioned functions of Vinexin-β, provide the inhibitor of Vinexin-β in preparation prevention, alleviate and/or treat the application in the medicine of cerebral apoplexy.
A medicine for neuroprotective function, comprises the inhibitor of Vinexin-β.
Prevention, alleviation and/or treatment cerebral apoplexy a medicine, comprise the inhibitor of Vinexin-β.
The inhibitor of described Vinexin-β is preferably the rna interference vector of siRNA, Vinexin-β gene of Vinexin-β gene, the one in the antibody of Vinexin-β and other inhibitor that Vinexin-β can be suppressed to express.
The present invention has following advantage and effect relative to prior art:
(1) the present invention finds the New function of Vinexin-β, and namely Vinexin-β can worsen the effect of cerebral apoplexy.
(2) worsening the function in cerebral apoplexy disease based on Vinexin-β, it is that development prevention, alleviation and/or the medicine for the treatment of cerebral apoplexy provide target.
(3) inhibitor of Vinexin-β can be used for preparing the medicine of neuroprotective function and prevention, alleviation and/or treatment cerebral apoplexy.
Accompanying drawing explanation
Fig. 1 is the assessment result figure of WT and Vinexin-β-KO murine cerebral ischemia/reperfusion injury severity.A is TTC coloration result figure, B is cerebral infarction volume statistics histogram, C is Neuroscore statistics histogram (*: p < 0.05vs wild-type I/R (24h) group, #:p < 0.05vs wild-type I/R (72h) group).
Fig. 2 is FluoroJadeB staining examine cerebral tissue infarct surrounding zone neuronal apoptosis situation measurement result figure.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
Animal for research and raising
Laboratory animal: select male, 11-12 week age, body weight is at 25-30g, background is the wild-type mice (WT of C57BL/6, purchased from Fukang bio tech ltd of China, Beijing, the certification of fitness number: 949431), Vinexin-β knock out mice (Vinexin-β-KO, purchased from Japanese RIKEN company, article No.: 01732).
Feeding environment: all experiment mices are all raised in angiocardiopathy institute of Wuhan University SPF level Experimental Animal Center.The large mouse feed of SRF level is purchased from Fukang bio tech ltd of China, Beijing.Rearing conditions: room temperature is between 22-24 DEG C, and humidity is between 40-70%, and it is 12h that light and shade replaces lighting hours, freely drinks water and ingests.
Embodiment 1 mouse brain Infarction Model (I/R) obtains
1. laboratory animal grouping: wild-type mice and Vinexin-β knock out mice, sets up Cerebral Infarction Model (I/R) by Cell transplantation.Be divided into 2 groups at random, often organize 10 mouse: wild-type mice I/R art group (WTI/R), Vinexin-β knock out mice I/R art group (KOI/R).
2. line brush cerebral infarction I/R performs the operation and adopts MCAO(middlecerebralarteryocclusion, middle cerebral artery occlusion) model manipulation flow process:
(1) capture mouse, use 3% isoflurane anesthesia mouse, 8% sodium sulphite sloughs the mouse hair of neck, and calvarium mouse hair operating scissors are cut rapidly, and 3% povidone iodine sterilization neck and calvarium skin 2 times, 75% alcohol takes off iodine 1 time.
(2) at the calvarium position cross sections of mouse, expose skull, peel off the reticular tissue of skull surface with tweezers gently.The fibre-optical probe xanthan gum of laser Doppler flowmetry is fixed on the position of bregma rear 2mm, left side 5mm.
(3) lain on the back by mouse fixing, neck median line otch, along nutator inner edge separating muscle and manadesma, is separated left common carotid (CCA), external carotid artery (ECA) and internal carotid artery (ICA).With arteriole folder temporarily folder close ICA, CCA, in the ligation of ECA distal end with cut an osculum, line bolt is sent into ICA by clip, when line bolt penetration depth stops to the blood flow decline power that is hampered at about 9-11mm, whole process must maintain the anus temperature of mouse at 37 ± 0.5 DEG C.
(4) from line bolt enter the cerebrovascular to blood flow decline be hampered power time timing, after 45min, line bolt is extracted, and by the ligation of ECA proximal part, unclamps rapidly CCA place bulldog clamp.Note observing restoration of blood flow situation, select blood flow to decline more than 75%, the mouse that restoration of blood flow reaches more than 70% includes experiment in.
(5) sew up mouse neck and skin of head, and to sterilize wound with povidone iodine.After operation terminates, be placed on by mouse in incubator, case temperature maintains 28 DEG C, and feedwater and feed, draw materials at 24h, 72h respectively.
Embodiment 2 Cerebral Infarction Model (I/R) mouse brain Infarction volume measures
The evaluation index of cerebral ischemia/reperfusion injury severity mainly comprises infarction of brain volume and Neuroscore, these indexs all with the positive correlation of ischemia/reperfusion injury severity.
(1) 24h, 72h carry out neural function and neurological deficit score before drawing materials after surgery respectively;
(9 points of systems) is improved one's methods based on Berderson Neuroscore:
0 point: the symptom that impassivity is impaired;
1 point: when carrying tail, offside forelimb is curled, or can not arrive Ipsilateral forelimb completely;
2 points: offside shoulder adduction when carrying tail;
3 points: horizontal sliding: when promoting to offside, resistance declines;
4 points: can be spontaneous to all directions motion, but only to turn to offside when de-tail;
5 points: turn-take during autonomic movement or only to turn;
6 points: without autokinetic movement, the only motion when stimulating;
7 points: without autokinetic movement, also without motion during stimulation;
8 points: the death relevant with cerebral ischemia.
(2) capture mouse, abdominal injection 3% vetanarcol anesthetized mice, gets brain.
(3) cerebral tissue taken off is put into 1mm mouse brain mould, be placed in-20 DEG C of refrigerators frozen.
(4) cerebral tissue 2,3, 5-Triphenyltertrazoliumchloride (2,3,5-Triphenyltetrazoliumchloricej, TTC) dyeing: take out cerebral tissue from-20 DEG C of refrigerators, be cut into 1mm slab immediately, cut 7 altogether.Section is placed in 10mL2%TTC solution immediately, 37 DEG C of constant-temperature incubation 10min.In bright red after normal cerebral tissue's dyeing, and infarcted region is pale asphyxia.
(5) fix brain tissue slice with 10% neutral formalin solution, substantially take pictures.
(6) cerebral infarction volume computing (Image-ProPlus6.0 software): Infarction volume %=(contralateral hemispheres volume-non-Infarction volume in infarct side)/(contralateral hemispheres volume × 2) × 100%;
Total Infarction volume is respective 7 large brain section result data sums.
TTC is fat-soluble photaesthesia mixture, and it is the proton acceptor of pyridine in respiratory chain-nucleotide structure enzyme system, and with the dehydrogenase reaction in healthy tissues and taking on a red color, and in ischemic tissue, dehydrogenase activity declines, and can not react, in pale asphyxia.
TTC coloration result is as shown in Figure 1A and B, through the Vinexin-β-KO mouse Infarction volume comparatively wild-type mice reduction after 24 hours of I/R ischemic 45min Reperfu-sion, and this provide protection still continues at I/R for postoperative 72 hours, cerebral tissue infarct is all lower than wild-type mice; And Neuroscore is at I/R postoperative 24 hours, 72 hours all low than wild-type mice (Fig. 1 C).Show that the disappearance of Vinexin-β gene can reduce the infarction of brain volume of the cerebral apoplexy mouse that ischemical reperfusion injury causes, can neuroprotective function.
Embodiment 3 cerebral tissue infarct surrounding zone neuronal apoptosis situation measures
1. cerebral tissue frozen section preparation
(1) mouse is captured, abdominal injection 3% vetanarcol anesthetized mice.
(2) open chest and expose heart, puncture into left ventricle with injection needles, cut off right atrium simultaneously.
(3) with PBS(0.01M, pH7.4) after 100mmHg pressure perfusion bleaches to liver, with 4% paraformaldehyde perfusion 15min.
(4) open cranium and take out mouse brain rapidly, after room temperature 4% paraformaldehyde, fix 6-8h.
(5) excise the olfactory bulb of cerebral tissue and cerebellum, then prolong median line and brain is divided into first latter two part, fix 15min again with previous stationary liquid.
(6) PBS(0.01M, the pH7.4 containing 30% sucrose is immersed in subsequently) in, 4 DEG C of refrigerators sink to the bottom and spend the night.
(7) 30% sucrose and OCT embedding medium are by 1:1(v/v) mix after, appropriate in embedding frame, the tissue of back is taken out, soak a little while in this embedding frame after gauze sucks liquid, be transferred to again and first added in another embedding frame of 2 OCT, the position of adjustment tissue, makes it just in time be positioned at the center of embedding frame.
(8) will contain the embedding frame of tissue, move in dry ice, make it be in horizontal position, slightly after a little while, continue to add OCT, certain height is organized in submergence, after OCT solidifies, is stored in the refrigerator of-80 DEG C as far as possible.
(9) frozen section of 5 μm is cut by the standard program of freezing microtome for subsequent use.
2.FJB(FluoroJadeB) dye
(1) ice is cut tissue slice and dry 1 hour in an oven;
(2) 1%NaOH+80% dehydrated alcohol 5min;
(3) 70% dehydrated alcohol 2min;
（4）ddH
2O2min；
(5) FlouroJadeB diluent (AG310, Millipore, Billerica, MA), room temperature, lucifuge 20min;
（6）ddH
2O1min×3；
(7) sheet 5-10min is dried in an oven;
(8) dimethylbenzene >1min;
(9) mounting, takes pictures.
As shown in Figure 2, the present embodiment have detected Vinexin-β-KO mouse and wild-type mice I/R postoperative 24 hours cerebral tissue infarct surrounding zone neuronal apoptosis situations to cerebral tissue infarct surrounding zone neuronal apoptosis situation measurement result.FluoroJadeB apoptosis detection display, it is obviously few than WT group mouse that Vinexin-β-KO organizes the apoptotic cell quantity of mouse, and when this shows Vinexin-β and neuronal cell ischemia-reperfusion, death is relevant.These results show, the disappearance of Vinexin-β can reduce the apoptosis of neuronal cell.
Result of study shows, in the damage that artery ischemia Reperfu-sion causes in the brain, mouse Infarction volume after Vinexin-β knocks out significantly reduces, neural function is clearly better, the nerve cell number of apoptosis also obviously reduces, this illustrates that Vinexin-β knocks out can neuroprotective function, improves cerebral apoplexy; Vinexin-β has important deterioration effect in cerebral apoplexy disease model.
Above-described embodiment is the present invention's preferably embodiment; but embodiments of the present invention are not restricted to the described embodiments; change, the modification done under other any does not deviate from spirit of the present invention and principle, substitute, combine, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (2)
1.Vinexin-β is as the application of drug targets in the medicine of screening neuroprotective function.
2.Vinexin-β is screening as drug targets the application alleviated and/or treat in the medicine of cerebral apoplexy disease.
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