CN117159579A - Application of membrane-associated protein MAGI3 in nerve regeneration - Google Patents
Application of membrane-associated protein MAGI3 in nerve regeneration Download PDFInfo
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Abstract
The application relates to application of membrane related protein MAGI3 in nerve regeneration, provides a new gene intervention target point-MAGI 3 site to effectively promote regeneration of axons after nerve injury, and provides a strategy for searching a treatment method of peripheral and central nerve injury to relieve pain of patients and recover nerve functions. The application discovers that the knockout of the MAGI3 gene can promote the regeneration of RGC axons after ischial nerve injury and optic nerve injury, and compared with the non-knockout of the MAGI3 gene, the length of the regeneration of the nerve axons after the knockout of the MAGI3 gene is longer, which indicates that substances which can be used for knockout or inhibition of the MAGI3 gene and inhibit the MAGI3 protein can be used as protective agents of retinal ganglion cells, such as: eye drops or intravitreal injection, etc. are used for the treatment of sciatic and optic nerve injuries.
Description
Technical Field
The disclosure relates to the technical field of nerve repair, in particular to application of membrane-associated protein MAGI3 in nerve regeneration.
Background
Damage to the nervous system is one of the main causes of global death and disability, and treatment of nerve damage is also a major problem in modern medicine. The lack of self-regenerating and repairing capabilities of the mammalian Central Nervous System (CNS), and therefore the inability to form a functional prominent link after injury, often leads to massive neuronal death, axonal degeneration, and permanent neurological loss. As the population ages, the incidence of neurological diseases increases year by year, and these diseases not only place a heavy economic burden on the patient's home, but also present a significant challenge to society.
The retina in the optic nervous system is a photosensitive tissue component of the central nervous system, and many different types of cells and complex structures are essential parts for the production and maintenance of retinal vision. Optic nerve damage diseases, such as glaucoma, can result in the inability of retinal ganglion cells (RetinaGanglionCells, RGCs) to regenerate their axonal parts and undergo massive apoptosis, and thus the inability of signals to pass from the retina to the brain, leading to serious consequences such as diminished color vision, reduced visual function, and even loss.
Nowadays, ocular pressure reduction and administration of neurotrophic substances are mostly adopted for optic nerve injury, however, due to limited optic nerve regeneration capacity and complexity of optic nerve injury, clinical treatment effects for optic nerve injury are very limited in clinic. In the current study, only limited numbers of nerve axons can be regenerated by targeting PTEN, mTOR, and KLFs genes and drug therapies. Therefore, it is very necessary to study the mechanism of optic nerve injury, and find new therapeutic targets that promote RGC survival and axon regeneration, with great clinical and social implications.
The membrane-associated guanylate kinase MAGUK (membrane-associated guanylate kinase) family of scaffold proteins MAGI3 plays an important role in maintaining normal cell morphology, cell adhesion and signal transduction.
In recent years, MAGI3 has been widely studied as a tumor suppressor, and MAGI3 often forms a complex with PTEN in cancer cells, and effects the anchoring of PTEN to cell membranes. However, the research on the mechanism of MAGI3 in regulating central nerve regeneration is still blank.
Earlier studies have clearly shown that MAGI3 is able to negatively regulate sciatic and optic nerve regeneration. Therefore, the important role of MAGI3 in regeneration after nerve injury is worth further investigation and transformation.
Disclosure of Invention
In order to solve the problems, the application provides an application of membrane-associated protein MAGI3 in nerve regeneration.
In one aspect of the application, an application of MAGI3 gene as an intervention target in promoting regeneration after nerve injury is provided.
In another aspect of the application, a method for said application is proposed, comprising: knocking out MAGI3 gene as gene intervention target.
In another aspect of the present application, a method for application is also provided, including: inhibiting the protein expression of the MAGI3 gene, which is a target of gene intervention of claim 1.
In another aspect of the present application, a neuroprotectant is provided, comprising a MAGI3-siRNA plasmid and a gene transfer vector, wherein the MAGI3-siRNA plasmid is introduced into injured nerve cells through the gene transfer vector, and is used for knocking out the MAGI3 gene, which is the gene intervention target.
In another aspect, the application also provides a neuroprotectant, which comprises a MAGI3-siRNA plasmid and a gene transfer vector, wherein the MAGI3-siRNA plasmid is introduced into injured nerve cells through the gene transfer vector and is used for inhibiting the protein expression of the MAGI3 gene serving as an interference target of the gene.
Preferably, the gene transfer vector is used for introducing MAGI3-shRNA plasmid into injured central nerve cells by AAV delivery technology, or is used for introducing MAGI3-siRNA plasmid into injured peripheral nerve cells by electrotransformation technology.
Preferably, the neuroprotective agent is in the form of an ophthalmic or intravitreal injection for therapeutic use.
The application has the technical effects that:
the application provides a new gene intervention target point-MAGI 3 locus to effectively promote the regeneration of axons after nerve injury, and provides a strategy for searching a treatment method of peripheral and central nerve injury to relieve pain of patients and recover nerve functions. The application discovers that the knockout of the MAGI3 gene can promote the regeneration of RGC axons after ischial nerve injury and optic nerve injury, and compared with the non-knockout of the MAGI3 gene, the length of the regeneration of the nerve axons after the knockout of the MAGI3 gene is longer, which indicates that substances which can be used for knockout or inhibition of the MAGI3 gene and inhibit the MAGI3 protein can be used as protective agents of retinal ganglion cells, such as: eye drops or intravitreal injection, etc. are used for the treatment of sciatic and optic nerve injuries.
Other features and aspects of the present disclosure will become apparent from the following detailed description of exemplary embodiments, which proceeds with reference to the accompanying drawings.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate exemplary embodiments, features and aspects of the present disclosure and together with the description, serve to explain the principles of the disclosure.
FIG. 1 shows an experimental flow chart for a sciatic nerve injury model of the present application;
FIG. 2 is a schematic diagram showing the comparison of regeneration of axons after DRG injury between the experimental group into which the MAGI3-siRNA of the present application was electrically transduced with DRG and the control group into which MAGI3 was not knocked down;
FIG. 3 shows statistical data of the length of sciatic nerve regeneration in FIG. 2 according to the present application;
FIG. 4 is a schematic view of the vitreous cavity injection and optic nerve injury site of the present application;
FIG. 5 shows a flow chart of an experiment for the optic nerve injury model of the present application;
FIG. 6 is a schematic diagram showing comparison of axonal regeneration after optic nerve injury between an experimental group of optic nerves knocked down with AAV-MAGI3-shRNA and a control group without knockdown of MAGI3 according to the present application;
fig. 7 shows length statistics for the optic nerve regeneration of fig. 6 according to the present application.
Detailed Description
Various exemplary embodiments, features and aspects of the disclosure will be described in detail below with reference to the drawings. In the drawings, like reference numbers indicate identical or functionally similar elements. Although various aspects of the embodiments are illustrated in the accompanying drawings, the drawings are not necessarily drawn to scale unless specifically indicated.
The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.
In addition, numerous specific details are set forth in the following detailed description in order to provide a better understanding of the present disclosure. It will be understood by those skilled in the art that the present disclosure may be practiced without some of these specific details. In some instances, well known means, elements, and circuits have not been described in detail so as not to obscure the present disclosure.
Through research, the important role of MAGI3 in regeneration after nerve injury is worthy of further research and transformation, and the MAGI3 can negatively regulate the regeneration of sciatic nerve and optic nerve.
The application discovers that the knockout of the MAGI3 gene can promote the regeneration of RGC axons after ischial nerve injury and optic nerve injury, and compared with the non-knockout of the MAGI3 gene, the length of the regeneration of the nerve axons after the knockout of the MAGI3 gene is longer, which indicates that substances which can be used for knockout or inhibition of the MAGI3 gene and inhibit the MAGI3 protein can be used as protective agents of retinal ganglion cells, such as: eye drops or intravitreal injection, etc. are used for the treatment of sciatic and optic nerve injuries.
The present application will be verified as follows.
1. Promotion of Sitting bone nerve by MAGI3
As shown in fig. 1, an experimental flow chart of the sciatic nerve injury model is shown. The sciatic nerve extrusion model is used for simulating traumatic injury of peripheral nervous system, and the high-efficiency gene transfection method for researching nerve regeneration, namely dorsal root nerve electricity-saving perforation technology, is used for electrically transducing MAGI3-siRNA plasmid in dorsal root ganglion (Dorsal Root Ganglia, DRG) containing neurons to knock down MAGI3. The sciatic nerve clamping operation was performed 2 days after the operation, and the nerve regeneration ability was detected and evaluated by measuring the length of nerve axon regeneration 3 days after the operation.
As shown in fig. 2, the MAGI3-siRNA electrotransduction DRG experiments showed that expression of knock-down MAGI3 (lower panel in fig. 2) promoted axon regeneration after DRG injury compared to the control group without knock-down MAGI3 (upper panel in fig. 2).
As shown in fig. 3, the length statistics for sciatic nerve regeneration in fig. 2 indicate that knocking down MAGI3 results in a significant increase in length of axonal regeneration following sciatic nerve injury.
In this example, the DRG is part of the peripheral nervous system (using siRNA electric transduction), and the RGC is part of the central system (using AAV-MAGI 3-shRNA). Thus, the present approach also contemplates that the MAGI3 site has great potential for repair or regeneration following nerve injury in other areas of the peripheral and central nerves. Reference may be made to the application of the present implementation to DRGs.
The scheme uses an optic nerve extrusion model to simulate traumatic injury of the central nervous system, the model only causes direct injury to RGC, and the regeneration result of optic nerve axons is clear and reliable. In addition, the present protocol uses adeno-associated virus (AAV) serotype 2 vectors as gene transfer vectors to transfect retinal knockdown MAGI3.AAV serotype 2 has higher retinal infection efficiency than other serotypes, and has the advantages of good safety, wide host range, low immunogenicity, long-term expression of carried therapeutic genes, and the like.
As shown in fig. 4, a schematic view of the site of intravitreal injection and optic nerve injury is shown. Adult wild-type mice, after exposing the left eye optic nerve, were clamped with a pair of spike forceps for about 2 seconds, resulting in compression of the optic nerve axons. The right eye was given as a control with sham surgery (without clamping optic nerve). The optic nerve clamping operation is performed two weeks after the AAV2-shMAGI3 is injected into the vitreous cavity of the eyeball, CTB is injected after 12 days of the ground after clamping for tracing the optic nerve bundles, and the optic nerve regeneration capacity is detected and evaluated by measuring the regeneration length and density of the nerve axons after 14 days of filling and sampling.
AAV2-shMAGI3 is mainly delivered by adopting AAV delivery technology.
This is because AAV delivery technology has become the primary platform for in vivo gene therapy delivery, with good safety and lower immunity. The most used AAV2 serotypes remain in the clinic, as are the most evidence of safety and efficacy of AAV2 serotypes.
2. MAGI3 optic nerve stimulation experiments
Fig. 5 is a schematic diagram of an experimental procedure of the optic nerve injury model.
As shown in fig. 6, knock-down of MAGI3 expression promoted optic nerve regeneration compared to the control group without knock-down MAGI 3; the red dotted line indicates the injury site.
As shown in fig. 7, the length statistics for optic nerve regeneration in fig. 6 indicate that knock-down of MAGI3 resulted in a significant increase in length of axonal regeneration following optic nerve injury.
See in particular the experimental procedure in "a".
Through the above experiments and data, it is shown that:
the gene intervention target point-MAGI 3 site can effectively promote the regeneration of axons after nerve injury, and provides a strategy for searching a treatment method of peripheral and central nerve injury so as to relieve pain of patients and recover nerve functions;
inhibiting MAGI3 is a gene intervention target point for promoting regeneration of retinal ganglion cell axons after optic nerve injury;
the important regulation and control function of MAGI3 in central nerve regeneration can be found after the MAGI3 is knocked down through an AAV2 virus delivery system, so that a new thought is provided for the treatment of promoting the central nerve regeneration;
the substances which knock out or inhibit MAGI3 genes and inhibit MAGI3 proteins can be used as protective agents of retinal ganglion cells.
In this scheme, the membrane-associated protein MAGI3 is applied to nerve regeneration, and the applied nerve injury can be used for treating sciatic nerve injury and optic nerve injury, or the MAGI3 locus is considered to have great potential for repairing or regenerating nerve injury at other parts of peripheral and central nerves. See in particular the application of the treatment assessment of the optic nerve or sciatic nerve in this example.
Claims (7)
1. The application of the MAGI3 gene serving as a gene intervention target in promoting regeneration after nerve injury.
2. The method for use of claim 1, comprising: knocking out MAGI3 gene as gene intervention target.
3. The method for use of claim 1, comprising: inhibiting the protein expression of the MAGI3 gene, which is a target of gene intervention of claim 1.
4. A neuroprotectant comprising a MAGI3-siRNA plasmid and a gene transfer vector, wherein the MAGI3-siRNA plasmid is introduced into injured nerve cells via the gene transfer vector, for knocking out the MAGI3 gene, which is the gene intervention target of claim 1.
5. A neuroprotective agent comprising a MAGI3-siRNA plasmid and a gene transfer vector, wherein the MAGI3-siRNA plasmid is introduced into injured nerve cells via the gene transfer vector for inhibiting protein expression of the MAGI3 gene, which is a gene intervention target of claim 1.
6. The gene transfer vector of claim 4 or 5, wherein the MAGI3-shRNA plasmid is introduced into injured central nerve cells using AAV delivery technology, or wherein the MAGI3-siRNA plasmid is introduced into injured peripheral nerve cells using electrotransport technology.
7. The neuroprotective agent of claim 4 or 5 for therapeutic use in the form of an ophthalmic or intravitreal injection.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310907115.8A CN117159579A (en) | 2023-07-24 | 2023-07-24 | Application of membrane-associated protein MAGI3 in nerve regeneration |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310907115.8A CN117159579A (en) | 2023-07-24 | 2023-07-24 | Application of membrane-associated protein MAGI3 in nerve regeneration |
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| CN202310907115.8A Pending CN117159579A (en) | 2023-07-24 | 2023-07-24 | Application of membrane-associated protein MAGI3 in nerve regeneration |
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