CN105963683A - Application of Sirt1 in repairing corneal nerve injury - Google Patents

Application of Sirt1 in repairing corneal nerve injury Download PDF

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Publication number
CN105963683A
CN105963683A CN201610505085.8A CN201610505085A CN105963683A CN 105963683 A CN105963683 A CN 105963683A CN 201610505085 A CN201610505085 A CN 201610505085A CN 105963683 A CN105963683 A CN 105963683A
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sirt1
mir
corneal
agonist
application
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王晔
牟晓峰
张蓉
慕莹
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Qingdao Central Hospital
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract

The invention provides application of Sirt1 in repairing corneal nerve injury. It is discovered herein that Sirt1 may promote the repairing of corneal nerve injury and may also promote the preparing of corneal epithelial injury as well as the axonal growth of trigeminal ganglion cells; the Sirt1 may be used to culture trigeminal ganglion cells, repair persistent corneal epithelial defect, repair diabetic corneal nerve injury and repair nervous keratitis. Moreover, corneal nerve injury can be more effectively repaired by the joint use of silencing signal regulator 1 and miR-182-5p agonist.

Description

Sirt1 application in corneal nerve damage is repaired
Technical field
The invention belongs to treatment of eye disorders technical field, be specifically related to the reticent signals-modulating factor 1 (Sirt1) Application in corneal nerve damage is repaired.
Background technology
Cornea is a kind of avascular hyaline tissue, and its nutrient substance is essentially from tear, aqueous humor and neural fibre Dimension.Cornea contains abundant nerve fiber, is one of the most intensive tissue of people's nerves within the body, for hot and cold, Bitterly, press etc. and to have the sensation of acumen.Corneal nerve is sent by ophthalmic branch of trigeminal nerve, is maintaining cornea tissue, The especially aspect such as corneal epithelium function and dissection integrity plays an important role.Can cause after corneal nerve damage Corneal sensation is gone down, and causes neurotrophic corneal epithelium pathological changes, main performance include epithelial erosion repeatedly, Epithelium regeneration is slow, persistence epithelial defect, ulcer and persistent inflammation reaction etc..
Corneal nerve belongs to peripheral nervous, has regeneration capacity.But, the neuranagenesis of usual cornea cannot not be complete Complete.The regeneration of corneal nerve has two kinds: one be by the int nerve of wound circumference and wound again Raw essential layer nerve goes out shoot regeneration, another kind be by the nerve trunk that wound circumference is thick in succession send thin and in Etc. thick nerve fiber, this is a kind of essential layer and the real regeneration of upper underlying nerve.Scholar is had to find cornea Neuranagenesis is divided into degeneration occurs in a short time in two periods, the first all nerves in impingement, simultaneously can See the thick and intensive neural axis of clump under wound circumference intact epithelial, be perpendicular to edge of wound and walk OK；Next to that the appearance of the degeneration of wound poloidal axis rope and second filial generation axon, these axons from edge of wound or The upper subcutaneous axon of the regeneration of nearly edge of wound.
Along with extensively carrying out of the operated eyes such as corneal ametropia operation, corneal graft and cataract, postoperative institute The corneal nerve damage problem shown presents the most day by day, the lasting epithelium caused due to corneal nerve damage Defect and epithelium repeatedly strip off, and considerably increase the risk that eye infects, and have become as a kind of potential Blinding pathological changes.Due to the infringement of corneal nerve, cause nutrition and the metabolism generation obstacle of cornea, be to draw Play keratopathy recurrent exerbation, it is difficult to the basic reason for the treatment of.
The treatment of corneal nerve damage reparation at present relies primarily on medicine, such as nerve growth factor (NGF) eye dripping Liquid.It addition, the persistent corneal epithelial defects caused for corneal nerve damage, the most a lot of symptomatic treatments, Such as tear substitute, corneal contact lens, tarsorrhaphy, somatomedin, autoserous application etc..Closely Occur in that again the modus operandis such as Transplantation of amniotic membrane and limbal stem cells transplantation over Nian, promote persistent corneal The healing of epithelial defect, but these Therapeutic Method are little for the injury repairing effect of corneal nerve, fail The problem fundamentally solving corneal nerve regeneration.Therefore, the new factor promoting corneal nerve regeneration is found With approach, clinical treatment corneal injury reparation had positive potential therapeutic potential.
Summary of the invention
It is an object of the invention to provide the reticent signals-modulating factor 1 (Sirt1) in corneal nerve damage is repaired Application, and the reticent signals-modulating factor 1 is in corneal nerve regeneration, persistent corneal epithelial shortage, diabetes The treatment of keratopathy, nerve keratitis treatment in application.
One aspect of the invention is to provide the reticent signals-modulating factor 1 (Sirt1) and repaiies preparing corneal nerve damage Application in copy；
The present invention also provides for the reticent signals-modulating factor 1 and miR-182-5p agonist simultaneously and is used in combination and makes Standby corneal nerve damage repairs the application in goods；
Preferred as embodiment, in goods, the concentration of the reticent signals-modulating factor 1 is preferably 20-50ng/ μ l； MiR-182-5p agonist preferred concentration is 0.1-0.5nmol/ml,
In corneal nerve damage reparation, the reparation to ophthalmic branch of trigeminal nerve accounts for Main Function, therefore In vitro culture three Fork ganglionic cell, and observe the reticent signals-modulating factor 1 impact on trigeminal ganglion neuron axon growth Most important.
Therefore, another aspect of the invention is to provide the reticent signals-modulating factor 1 and cultivates nervi trigeminus in preparation Ganglion cell cultivates the application in goods,
Above-mentioned application, wherein the reticent signals-modulating factor 1 and miR-182-5p agonist is used in combination；
Another aspect of the present invention provides a kind of method cultivating trigeminal ganglion neuron, is to cultivate trident god Sirt1 is added in the culture medium of ganglion cell；
Preferred as embodiment, the interpolation concentration of Sirt1 is 20-100ng/ml,
Further, culture medium has been also added with miR-182-5p agonist；
Preferred as embodiment, the interpolation concentration of miR-182-5p agonist is 0.1-0.5nmol/ml；
Present invention discover that Sirt1 can not only promote corneal nerve damage reparation, moreover it is possible to promote the damage of corneal epithelium Repair, also can promote trigeminal ganglion neuron axon growth simultaneously.Can be used for trigeminal ganglion neuron cultivate, The reparation of persistent corneal epithelial defects, the reparation of diabetes corneal nerve infringement, the repairing of nerve keratitis Multiple.
Accompanying drawing explanation
Fig. 1: the Sirt1 facilitation figure to trigeminal ganglion neuron axon growth.At trigeminal ganglion neuron Culture medium in add Sirt1, the 20ng/ml Sirt1 of variable concentrations and can effectively facilitate trigeminal ganglion neuron axle Exsule length.
Fig. 2: Sirt1 is used in combination promotion mice trigeminal ganglion neuron aixs cylinder life with miR-182-5p agonist Long figure.In the culture medium of trigeminal ganglion neuron, add 20ng/ml Sirt1, add in culture fluid simultaneously Adding 0.1 or after the miR-182-5p agonist of 0.5nmol/ml, trigeminal ganglion neuron axon length significantly increases Add, and the branch of aixs cylinder dramatically increases.
Fig. 3: exogenous interpolation Sirt1 affects figure to what normal mouse cornea corneal nerve damage was repaired.Under conjunctiva Injection 50ng Sirt1 can effectively facilitate the regeneration of corneal nerve.
Fig. 4: Sirt1 affects figure to miR-182-5p expression.
Fig. 5: Sirt1 and miR-182-5p agonist or inhibitor are used in combination skin lesion on normal mouse cornea The figure that wound is repaired.Subconjunctival injection 50ng Sirt1 can effectively facilitate the injury repairing of corneal epithelium；Sirt1 joins Conjunction miR-182-5p agonist group is compared with Sirt1 group, and it promotes that the effect that corneal epithelial wound is repaired is brighter Aobvious.And Sirt1 associating miR-182-5p inhibitor group is compared with Sirt1 group, it promotes that corneal epithelial wound is repaiied Multiple effect is obviously reduced.
Detailed description of the invention
The present invention adds the Sirt1 (such as 20 of doses in the culture medium of mice trigeminal ganglion neuron Ng/ml), can not only promote that trigeminal ganglion neuron grows, and remarkably promote trigeminal ganglion neuron aixs cylinder Growth；Thus facilitate the present invention.
The reticent signals-modulating factor 1 is present in the yeast chromosome matter silencer Sir2 autoploid of mammal, is A kind of histon deacetylase (HDAC) relying on NAD+.
MiR-182 is positioned No. 7 chromosomes (7q32.2) of people, defines one with miR-96, miR-183 Gene cluster, its sequence is: 5 '-uuuggcaaugguagaacucacacu-3 '.MiR-182-5p agonist is to use Being chemically synthesized, and use the miRNA agonist of chemical modification, stability is higher, is appropriate to long-term MiRNA functional study, played a role by the simulation miRNA regulation expression of said target mrna. MiR-182-5p agonist has higher stability and miRNA facilitation effect in animal body.And can overcome The obstacles such as cells in vivo film, tissue are enriched in target cell.In zoopery can with whole body or local injection, The methods such as suction, medicine feed are administered, and the action effect persistent period is 6 weeks.
Below in conjunction with specific embodiments and the drawings, the present invention is described in detail
Embodiment 1:Sirt1 promotes mice trigeminal ganglion neuron axon growth
Application trigeminal ganglion neuron culture fluid (Culture medium, Invitrogen/Gibco, goods Number 21103-049), add B27 (10X) (Invitrogen/Gibco, article No. 17504-044).Cellar culture 1000 cells are seeded in 30mm culture dish, then in 5%CO by trigeminal ganglion neuron2With 37 DEG C Under conditions of cultivate, within every 3 days, more renew culture medium, add the Sirt1 factor simultaneously, after cultivating 9 days fixing carefully Born of the same parents, use neuronal specificity mark Tubulin III dyeing, observe trigeminal ganglion neuron axon growth feelings Condition.As it is shown in figure 1, after adding the Sirt1 of 20-50ng/ml in culture fluid, trigeminal ganglion neuron aixs cylinder is long Degree dramatically increases, and the branch of aixs cylinder dramatically increases, and illustrates that Sirt1 can effectively facilitate trigeminal ganglion neuron axle Exsule length.
Embodiment 2:Sirt1 and miR-182-5p agonist are used in combination promotion mice trigeminal ganglion neuron axle Exsule length
Application trigeminal ganglion neuron culture fluid (Culture medium, Invitrogen/Gibco, goods Number 21103-049), add B27 (10X) (Invitrogen/Gibco, article No. 17504-044).Cellar culture 1000 cells are seeded in 30mm culture dish by trigeminal ganglion neuron, add Sirt1 (20 in ware Ng/ml), then in 5%CO2Cultivate under conditions of 37 DEG C, within every 3 days, more renew culture medium, add concentration It is the miR-182-5p agonist of 0.1 or 0.5nmol/ml, after cultivating 9 days, fixes cell, use neuron Specific marker Tubulin III dyes, and observes trigeminal ganglion neuron axon growth situation.As in figure 2 it is shown, After culture fluid adds the miR-182-5p agonist of 0.1 or 0.5nmol/ml, trigeminal ganglion neuron aixs cylinder Length dramatically increases, and the branch of aixs cylinder dramatically increases, and illustrates that Sirt1 with miR-182-5p agonist is combined and makes With effectively facilitating trigeminal ganglion neuron axon growth.
Embodiment 3: the impact that normal mouse cornea corneal nerve damage is repaired by exogenous interpolation Sirt1
12 C57BL/6 mices (6-8 week old) are randomly divided into matched group and experimental group, use 3mm ring Bore and epithelium scraper strikes off the epithelium in mice cornea of right eye central authorities 3mm region, control group mice right eye simultaneously Subconjunctival injection 5 μ l PBS, experimental mice conjunctiva of right eye hemostasis 50ng Sirt1 (are dissolved in 5 μ l PBS molten In liquid), within latter 21 days, use neuronal specificity mark Tubulin III dyeing to observe each group of mice in modeling Corneal nerve regeneration situation, representative photo is shown in Fig. 3.As it is shown on figure 3, subconjunctival injection 50ng Sirt1 energy Effectively facilitate the regeneration of corneal nerve.
The impact of embodiment 4:Sirt1 suppression miR-182-5p expression
Application trigeminal ganglion neuron culture fluid (Culture medium, Invitrogen/Gibco, goods Number 21103-049), add B27 (10X) (Invitrogen/Gibco, article No. 17504-044).Cellar culture Trigeminal ganglion neuron, by 105Individual cell is seeded in 60mm culture dish, then in 5%CO2 and 37 DEG C Under conditions of cultivate 24h, in ware add Sirt1 (20ng/ml), respectively at 5%CO2 and the condition of 37 DEG C Under hatch cultivation 0min, 15min and 30min after, RNA the reverse transcription of extracting each group of sample are cDNA, The expression of miR-182-5p in each group of application real time quantitative PCR method detection.As shown in Figure 4, Sirt1 Effect 15min and 30min, all can substantially suppress the expression of miR-182-5p.
Embodiment 5:Sirt1 and miR-182-5p agonist or inhibitor are used in combination on normal mouse cornea The impact of skin injury repairing
24 C57BL/6 mices (6-8 week old) are randomly divided into four groups: PBS control group, Sirt1 group, Sirt1 associating miR-182-5p agonist group, Sirt1 combine miR-182-5p inhibitor group.Use 3mm ring Bore and epithelium scraper strikes off the epithelium in mice cornea of right eye central authorities 3mm region, PBS control group mice simultaneously Conjunctiva of right eye hemostasis 5 μ l PBS, Sirt1 group mice conjunctiva of right eye hemostasis 50ng Sirt1 (is dissolved in 5 μ l PBS), Sirt1 combines miR-182-5p agonist group mice conjunctiva of right eye hemostasis 50ng Sirt1 and 0.3nmol MiR-182-5p agonist (is dissolved in 5 μ l PBS), and Sirt1 combines miR-182-5p agonist group mice right eye Subconjunctival injection 50ng Sirt1 and 0.3nmol miR-182-5p inhibitor (being dissolved in 5 μ l PBS), in modeling Rear 24,48 and 72h use photograph under fluorescein sodium dyeing and slit lamp respectively, observe the epithelium of each group of mice The situation of injury repairing, Fig. 5 is shown in by representative slit lamp observation photo.As it is shown in figure 5,48h after Jian Mo, knot Film hemostasis 50ng Sirt1 can effectively facilitate the injury repairing of corneal epithelium；Sirt1 associating miR-182-5p swashs Dynamic agent group is compared with Sirt1 group, and it promotes that the effect of corneal epithelial wound reparation becomes apparent from.And Sirt1 connection Conjunction miR-182-5p inhibitor group is compared with Sirt1 group, and it promotes that the effect of corneal epithelial wound reparation significantly subtracts Weak.

Claims (10)

1. the reticent signals-modulating factor 1 application in preparing corneal nerve damage reparation and recycled product.
2. the reticent signals-modulating factor 1 and miR-182-5p agonist prepare corneal nerve damage reparation with Application in recycled product.
Apply the most as claimed in claim 1, it is characterised in that in described goods reticent signals-modulating because of The concentration of son 1 is 20-100ng/ μ l.
Apply the most as claimed in claim 1, it is characterised in that in described goods, miR-182-5p swashs Dynamic agent concentration is 0.04-0.1nmol/ μ l.
5. the reticent signals-modulating factor 1 application in trigeminal ganglion neuron is cultivated.
6. the reticent signals-modulating factor 1 and miR-182-5p agonist is used in combination at trigeminal ganglion neuron Application in cultivation.
7. the method cultivating trigeminal ganglion neuron, it is characterised in that described method is to cultivate three The culture medium of fork ganglionic cell adds Sirt1.
8. method as claimed in claim 7, it is characterised in that described method is to cultivate nervi trigeminus The culture medium of ganglion cell has been also added with miR-182-5p agonist.
9. method as claimed in claim 7, it is characterised in that it is 20-100 that described Sirt1 adds concentration ng/ml。
10. method as claimed in claim 7, it is characterised in that described miR-182-5p agonist adds Adding concentration is 0.1-0.5nmol/ml.
CN201610505085.8A 2016-04-12 2016-06-30 Application of Sirt1 in repairing corneal nerve injury Withdrawn CN105963683A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2938765A1 (en) * 2008-11-26 2010-05-28 Isp Investments Inc Cosmetic composition, useful e.g. to prevent skin manifestations of aging, comprises peptide hydrolyzate of vine leaves (Vitis vinifera) as sirtuin protein activator, alone or in combination with other active ingredient, in medium
WO2011035018A2 (en) * 2009-09-18 2011-03-24 Fate Therapeutics, Inc. Suicide ready cells
CN102239149A (en) * 2008-10-06 2011-11-09 约翰·霍普金斯大学 Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102239149A (en) * 2008-10-06 2011-11-09 约翰·霍普金斯大学 Quinoline compounds as inhibitors of angiogenesis, human methionine aminopeptidase, and sirt1, and methods of treating disorders
FR2938765A1 (en) * 2008-11-26 2010-05-28 Isp Investments Inc Cosmetic composition, useful e.g. to prevent skin manifestations of aging, comprises peptide hydrolyzate of vine leaves (Vitis vinifera) as sirtuin protein activator, alone or in combination with other active ingredient, in medium
WO2011035018A2 (en) * 2009-09-18 2011-03-24 Fate Therapeutics, Inc. Suicide ready cells

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
TATSUYA MIMURA等: "The role of SIRT1 in ocular aging", 《EXPERIMENTAL EYE RESEARCH》 *
YE WANG等: "Overexpression of SIRT1 Promotes High Glucose–Attenuated Corneal Epithelial Wound Healing via p53 Regulation of the IGFBP3IGF-1RAKT Pathway", 《IVOS》 *
YE WANG等: "SIRT1-responsive microRNA-182 contributes to a regulatory loop for recovery of peripheral nerve injury in experimental diabetic neuropathy", 《INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE》 *
YUNHAI DAI等: "Neuropeptide FF Promotes Recovery of Corneal Nerve Injury Associated With Hyperglycemia", 《IVOS》 *

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