CN110714068A - Application of membrane protein molecule ErbB4 in preparation of medicines for treating cerebral ischemic injury - Google Patents
Application of membrane protein molecule ErbB4 in preparation of medicines for treating cerebral ischemic injury Download PDFInfo
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- CN110714068A CN110714068A CN201911114370.7A CN201911114370A CN110714068A CN 110714068 A CN110714068 A CN 110714068A CN 201911114370 A CN201911114370 A CN 201911114370A CN 110714068 A CN110714068 A CN 110714068A
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- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1883—Neuregulins, e.g.. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2871—Cerebrovascular disorders, e.g. stroke, cerebral infarct, cerebral haemorrhage, transient ischemic event
Abstract
The invention provides an application of a membrane protein molecule ErbB4 in preparing a medicament for treating cerebral ischemic injury, which comprises the following aspects: and (3) establishing a damage model, and carrying out drug treatment prepared from the membrane protein molecule ErbB4 on the damage model, namely promoting the total expression and activity of ErbB4 in the damage model, so that the damage of ischemia on neurons can be inhibited. The invention also provides a medicament for treating cerebral ischemic injury, which comprises regulatory protein NRG1 for promoting the total expression and activity of a membrane protein molecule ErbB 4. The invention also provides a method for promoting the total expression and activity of the membrane protein molecule ErbB4, which comprises the following steps: (1) establishing a cerebral ischemia model; (2) observing total expression and active fragment expression of ERBB4 in a cerebral ischemia model; (3) whether the activity and expression regulation of the membrane molecule ErbB4 can affect cholesterol synthesis; (4) increasing NRG1 in brain ischemia models promoted total ERBB4 expression and activity. The application of the invention inhibits the damage of ischemia to neurons and has protective effect on cerebral ischemia damage.
Description
Technical Field
The invention belongs to the field of molecular biology and biological medicine, and particularly relates to an application of a membrane protein molecule ErbB4 in preparation of a medicine for treating cerebral ischemic injury, and a method for promoting total expression and activity of a membrane protein molecule ErbB 4.
Background
Statistical data in stroke prevention and treatment reports in China (2018) indicate that the incidence of stroke in China has sharply risen in the past 30 years, and the low-income groups have a rapid growth tendency, obvious gender and regional differences and a youthful trend. The report suggests that the stroke prevention and treatment project is not slow, and scientific research connotation of stroke prevention and treatment work must be further strengthened.
Ischemic stroke accounts for about 80% of patients with stroke. Ischemic stroke refers to sudden decrease in blood perfusion or complete interruption of blood supply to local blood supply arteries of brain tissue, which leads to decrease or complete stop of blood supply, oxygen supply, sugar supply, and the like of the tissue, and cell destruction and disintegration. Therefore, reestablishment of blood flow or increased blood supply to the ischemic area is a prerequisite for ischemic repair of brain tissue. It is essential for the ischemic brain tissue to repair the damage by reestablishing blood flow or increasing blood supply to the ischemic area, however, physicians have found that the main factor of the damage to the brain tissue, not the ischemia itself, but the damage caused by the cells in the part of the brain tissue in which the blood supply is restored, is called "cerebral ischemia-reperfusion damage". The pathological damage mechanism after cerebral ischemia is very complex, the cascade and network relation among various damage mechanisms is not clear, and the clinical test of candidate drugs developed aiming at a certain target point in the cerebral ischemia damage mechanism fails. Therefore, there is a need to search for new preventive and therapeutic targets, drugs and methods for treating or preventing cerebral ischemic injury.
Disclosure of Invention
The invention aims to solve the technical problems of providing an application of a membrane protein molecule ErbB4 in preparing a medicament for treating cerebral ischemic injury, and a method for promoting the total expression and activity of the membrane protein molecule ErbB4 so as to solve the problems in the background art.
In order to solve the technical problems, the embodiment of the invention provides application of a membrane protein molecule ErbB4 in preparing a medicament for treating cerebral ischemic injury.
Further, the application of the membrane protein molecule ErbB4 in preparing the medicament for treating the cerebral ischemic injury comprises the following aspects: and (3) establishing a damage model, and carrying out drug treatment prepared from the membrane protein molecule ErbB4 on the damage model, namely promoting the total expression and activity of ErbB4 in the damage model, so that the damage of ischemia on neurons can be inhibited.
The embodiment of the invention also provides a medicament for treating cerebral ischemic injury, which is characterized by comprising regulatory protein NRG1 for promoting the total expression and activity of a membrane protein molecule ErbB 4.
The embodiment of the invention also provides a method for promoting the total expression and activity of the membrane protein molecule ErbB4, which is characterized by comprising the following steps: (1) establishing a cerebral ischemia model; (2) observing total expression and active fragment expression of ERBB4 in a cerebral ischemia model; (3) whether the activity and expression regulation of the membrane molecule ErbB4 can affect cholesterol synthesis; (4) increasing NRG1 in brain ischemia models promoted total ERBB4 expression and activity.
Further, the cerebral ischemia model in the step (1) can adopt one of a rat MCAO/R injury model or an OGD/R cell injury model.
Wherein, the establishment of the rat MCAO/R injury model comprises the following steps: weighing a mouse, carrying out intraperitoneal injection anesthesia on 10% chloral hydrate, fixing, carrying out a median incision on the neck, separating subcutaneous tissues by using an ophthalmic forceps, exposing the trachea of the rat, separating the right common carotid artery, and separating the internal carotid artery and the external carotid artery respectively, wherein attention is paid to avoid damaging the vagus nerve in the separation process; sequentially dissociating from the bifurcation of the common carotid artery to the head end, simultaneously ligating the proximal end of the common carotid artery on the right side to dissociate the main trunk for later use, then separating the internal and external carotid arteries on the right side, fixing the internal and external carotid arteries by a nondestructive artery clamp, making an incision near the distal end of the ligation part of the common carotid artery, rapidly inserting a suture holding plug into the incision by using a micro-forceps, and pushing the suture holding plug for 18-20mm to cause the existence of a resistance, thereby indicating that the head end of the suture plug passes through the initial part of the middle cerebral artery and blocking the source of partial blood flow of the middle artery; ligating and fixing the blood vessel at the far end of the incision to prevent the thread plug from falling off, and suturing the skin of the rat; after the rat is ischemic for 2 hours, gently pulling the remained thread head to the incision of the common carotid artery to realize the blood flow reperfusion of the middle cerebral artery; during the operation, the temperature of the rat anus is maintained between 36.5 and 37.5 ℃, and the steps of the sham operation group are the same except that no plug is inserted; and (3) judging whether the model is successfully made according to a model making success judgment standard, and respectively scoring when the rat is awake after the operation and before and after the reperfusion by referring to a Zea Long scoring standard: 0 minute: no symptoms of nerve damage; 1 minute: the left front paw cannot be fully extended; and 2, dividing: turning to the left side; and 3, dividing: when walking, the walking stick is inclined towards the left side; and 4, dividing: it is unable to walk spontaneously.
The method for establishing the OGD/R cell damage model comprises the following steps: the model is established by adopting a three-gas incubator, and CO in the three-gas incubator is accurately controlled by directly introducing N22And O2The concentration is increased, and sugar in a neuron culture medium is deprived, so that an environment of oxygen and sugar deficiency of cultured neurons is created, and the condition of cerebral ischemia in a body is simulated; inoculating the hippocampal neuron suspension into a cell culture dish for culture and maturation, discarding a cell culture medium in the culture dish and replacing the cell culture medium with a sugar-free culture medium; then placing in a low oxygen workstation containing 1% O2、5%CO2、94%N2Carrying out anoxic culture for 45 min; and (4) removing the culture dish from the three-gas incubator, then replacing the sugar-free culture medium with a sugar-containing cell culture medium, and placing the culture medium in the original cell incubator for normal culture for 0h, 6h, 12h, 18h and 36h for detection.
The technical scheme of the invention has the following beneficial effects: according to the invention, by utilizing a cerebral ischemia injury model and an oxygen sugar deprivation/reoxygenation injury model induced by arterial embolism/reperfusion in a rat, the reduction of total expression and active fragment expression of ERBB4 after ischemia injury is observed for the first time, and the application of a membrane protein molecule ErbB4 in the preparation of a medicament for treating cerebral ischemia injury inhibits the injury of ischemia to neurons by promoting the expression of the membrane protein molecule ErbB 4; the medicine for treating cerebral ischemia injury comprises regulatory protein NRG1 for promoting total expression and activity of membrane protein molecule ErbB4, wherein the NRG1 can promote total expression and activity of ErbB 4; the promotion method of the total expression and activity of the membrane protein molecule ErbB4 increases NRG1 in a cerebral ischemia model, promotes the total expression and activity of ERBB4, and promotes the increase of cholesterol synthesis, thereby inhibiting the damage of ischemia to neurons, inhibiting the behavioral change caused by the ischemia damage, and having a protective effect on the cerebral ischemia damage.
Drawings
FIG. 1 shows the expression and activity changes of membrane molecule ErbB4 in the rat cerebral ischemia injury model of the present invention; wherein, FIG. 1A is a TTC staining pattern of brain tissue section; FIG. 1B is a graph showing the effect of repeated perfusion at different times on the expression of ErbB4 mRNA in hippocampal tissues; FIG. 1C is a graph showing the effect of repeated perfusion at different times on the expression of ErbB4 protein in hippocampal tissues; FIG. 1D is a gray scale histogram of ErbB4 protein expression; # P < 0.05, # P < 0.001vs. Sham. P < 0.05, # P < 0.01 vs. MCAO/R0 h.
FIG. 2 is a graph of an assay of the inhibition of ischemic neuronal damage by the promotion of ErbB4 activity in accordance with the present invention; wherein, FIG. 2A is the effect of OGD/R injury at different times on primary cultured hippocampal neuron ErbB4 mRNA expression; FIG. 2B is a gray scale histogram of ErbB4 protein expression; FIG. 2C is a schematic representation of the effect of ErbB4 siRNA and NRG1 on OGD/R injury primary culture hippocampal neuronal cell viability; FIG. 2D is a schematic representation of the effect of ErbB4 siRNA and NRG1 on apoptosis following primary culture hippocampal OGD/R injury; # # P < 0.01, # # # P < 0.001vs. control, # P < 0.05, # P < 0.01, # P < 0.001vs. OGD/R0 h.
FIG. 3 is a graph of an assay of the invention for promoting ErbB4 activity to increase cholesterol synthesis and inhibit damage to ischemic neurons; wherein, FIG. 3A is an expression diagram of ErbB4 siRNA and NRG1 regulating ErbB4 protein (western blot detection); FIG. 3B is a schematic representation of the effect of ErbB4 siRNA and NRG1 on OGD/R damage on primary hippocampal cholesterol synthesis major enzyme expression; FIG. 3C is a gray scale histogram of ErbB4 siRNA and NRG1 regulated ErbB4 protein expression; # P < 0.05, # P < 0.001vs. control, # P < 0.05, # P < 0.01, # P < 0.001vs. OGD/R18 h.
Detailed Description
In order to make the technical problems, technical solutions and advantages to be solved by the present invention clearer, the following detailed description is given with reference to specific embodiments.
The embodiment of the invention provides an application of a membrane protein molecule ErbB4 in preparing a medicament for treating cerebral ischemic injury, which comprises the following aspects: and (3) establishing a damage model, and carrying out drug treatment prepared from the membrane protein molecule ErbB4 on the damage model, namely promoting the total expression and activity of ErbB4 in the damage model, so that the damage of ischemia on neurons can be inhibited.
The embodiment of the invention also provides a medicament for treating cerebral ischemic injury, which comprises regulatory protein NRG1 for promoting the total expression and activity of a membrane protein molecule ErbB 4.
The embodiment of the invention also provides a method for promoting the total expression and activity of the membrane protein molecule ErbB4, which is characterized by comprising the following steps: (1) establishing a cerebral ischemia model;
the cerebral ischemia model can adopt one of a rat MCAO/R injury model or an OGD/R cell injury model.
Wherein, the establishment of the rat MCAO/R injury model comprises the following steps: weighing a mouse, carrying out intraperitoneal injection anesthesia on 10% chloral hydrate, fixing, carrying out a median incision on the neck, separating subcutaneous tissues by using an ophthalmic forceps, exposing the trachea of the rat, separating the right common carotid artery, and separating the internal carotid artery and the external carotid artery respectively, wherein attention is paid to avoid damaging the vagus nerve in the separation process; sequentially dissociating from the bifurcation of the common carotid artery to the head end, simultaneously ligating the proximal end of the common carotid artery on the right side to dissociate the main trunk for later use, then separating the internal and external carotid arteries on the right side, fixing the internal and external carotid arteries by a nondestructive artery clamp, making an incision near the distal end of the ligation part of the common carotid artery, rapidly inserting a suture holding plug into the incision by using a micro-forceps, and pushing the suture holding plug for 18-20mm to cause the existence of a resistance, thereby indicating that the head end of the suture plug passes through the initial part of the middle cerebral artery and blocking the source of partial blood flow of the middle artery; ligating and fixing the blood vessel at the far end of the incision to prevent the thread plug from falling off, and suturing the skin of the rat; after the rat is ischemic for 2 hours, gently pulling the remained thread head to the incision of the common carotid artery to realize the blood flow reperfusion of the middle cerebral artery; during the operation, the temperature of the rat anus is maintained between 36.5 and 37.5 ℃, and the steps of the sham operation group are the same except that no plug is inserted; and (3) judging whether the model is successfully made according to a model making success judgment standard, and respectively scoring when the rat is awake after the operation and before and after the reperfusion by referring to a Zea Long scoring standard: 0 minute: no symptoms of nerve damage; 1 minute: the left front paw cannot be fully extended; and 2, dividing: turning to the left side; and 3, dividing: when walking, the walking stick is inclined towards the left side; and 4, dividing: it is unable to walk spontaneously.
The method for establishing the OGD/R cell damage model comprises the following steps: the model is built by adopting a three-gas incubator through directly introducing N2By accurately controlling CO in the three-gas incubator2And O2The concentration is increased, and sugar in a neuron culture medium is deprived, so that an environment of oxygen and sugar deficiency of cultured neurons is created, and the condition of cerebral ischemia in a body is simulated; inoculating the hippocampal neuron suspension into a cell culture dish for culture and maturation, discarding a cell culture medium in the culture dish and replacing the cell culture medium with a sugar-free culture medium; then placing in a low oxygen workstation containing 1% O2、5%CO2、94%N2Carrying out anoxic culture for 45 min; and (4) removing the culture dish from the three-gas incubator, then replacing the sugar-free culture medium with a sugar-containing cell culture medium, and placing the culture medium in the original cell incubator for normal culture for 0h, 6h, 12h, 18h and 36h for detection.
Observing total expression and active fragment expression of ERBB4 in a cerebral ischemia model;
the total protein and hydrolyzed fragment of the membrane molecule ErbB4 of the invention have obvious activity change in ischemia reperfusion injury neurons. Total protein expression of ErbB4 in brain tissue of ischemic rats and active fragments thereof (molecular weight 80X 10) compared to sham operated rats3KD) begins to decline; after 6h of reperfusion injury, there was a marked downward trend with prolonged reperfusion injury time, with minimal ErbB4 protein expression and activity at 12h of MCAO reperfusion injury and a rising response 24h after reperfusion injury, as shown in figure 1.
The relative molecular mass of the protein encoded by the ErbB4 gene was 180X 103KD, on the one hand, ErbB4 can be activated by ligands as tyrosine kinases, leading to activation of the corresponding signaling pathway; on the other hand, ErbB4 can be hydrolyzed by a series of specific proteases to produce a fragment containing tyrosine kinase activity with a relative molecular mass of 80X 103Membrane protein fragment of KD. The transmembrane fragment further hasThe gene is hydrolyzed and finally transported to nucleus to directly activate certain gene transcription, and the regulation of ErbB4 can regulate multiple links of ischemia injury pathology; thus, ischemic injury can be modulated by the agents of the invention by modulating ErbB 4.
Whether the activity and expression regulation of the membrane molecule ErbB4 can affect cholesterol synthesis;
the activity and expression regulation of the ErbB4 membrane molecule of the present invention can affect cholesterol synthesis, thereby regulating the survival of ischemia damaged cells. Cholesterol is an important component of biological membranes. Biofilms are absolutely important structures in vital activities, in which cholesterol is mainly present in free form. Higher levels in the plasma membrane of cells and fewer in the endoplasmic reticulum and other organelles. After ischemia of nerve cells, cholesterol outflow is increased, and membrane structure is destroyed, which is one of the causes of cell damage. Promoting cholesterol synthesis, and reducing cholesterol efflux can inhibit cell injury. SREBP-2 is mainly used for promoting the synthesis of cholesterol.
As shown in FIG. 3B, activation of the membrane molecule ErbB4 of the present invention induced SREBP-2 expression and the cholesterol synthesis pathway rate-limiting enzyme HMGCR, thereby promoting cholesterol synthesis and survival of injured neurons.
Increasing NRG1 in brain ischemia models promoted total ERBB4 expression and activity.
As shown in fig. 2 and fig. 3, compared with the normal control group, the protein expression level of ErbB4 is significantly reduced after OGD/R18h damages primary hippocampal neurons; compared with the OGD/R18h group, the protein expression level of ErbB4 after OGD/R18h injury is further reduced after the ErbB4 siRNA interferes with primary hippocampal neurons; and the protein expression of OGD/R18h + NRG1 group ErbB4 is obviously improved. The ErbB4 siRNA can obviously inhibit protein expression of ErbB4 after primary hippocampal OGD/R injury, and the protein expression of ErbB4 is obviously improved after being activated by NRG 1. In addition, the ErbB4 siRNA increases the apoptosis of OGD/R damaged primary culture hippocampal neurons, and the apoptosis is obviously reduced after the ErbB4 is activated, which indicates that the ErbB4 has a protective effect on cerebral ischemia-reperfusion damaged neurons.
While the foregoing is directed to the preferred embodiment of the present invention, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (7)
1. Application of membrane protein molecule ErbB4 in preparing medicine for treating cerebral ischemia injury is disclosed.
2. The use of the membrane protein molecule ErbB4 according to claim 1 in the manufacture of a medicament for the treatment of ischemic brain injury, comprising: an injury model is established, and the injury model is subjected to drug therapy of drugs for treating cerebral ischemic injury, namely the total expression and activity of ErbB4 are promoted in the injury model, so that the injury of ischemia on neurons can be inhibited.
3. A medicament for treating cerebral ischemic injury, which is characterized by comprising regulatory protein NRG1 for promoting total expression and activity of a membrane protein molecule ErbB 4.
4. A method for promoting the total expression and activity of the membrane protein molecule ErbB4, comprising the steps of: (1) establishing a cerebral ischemia model; (2) observing total expression and active fragment expression of ERBB4 in a cerebral ischemia model; (3) whether the activity and expression regulation of the membrane molecule ErbB4 can affect cholesterol synthesis; (4) increasing NRG1 in brain ischemia models promoted total ERBB4 expression and activity.
5. The method of promoting the total expression and activity of the membrane protein molecule ErbB4 according to claim 4, wherein the model of cerebral ischemia in step (1) is one of rat MCAO/R injury model or OGD/R cell injury model.
6. The method of promoting the total expression and activity of the membrane protein molecule ErbB4 of claim 5, wherein the model of rat MCAO/R injury is established by the steps of: weighing a mouse, carrying out intraperitoneal injection anesthesia on 10% chloral hydrate, fixing, carrying out a median incision on the neck, separating subcutaneous tissues by using an ophthalmic forceps, exposing the trachea of the rat, separating the right common carotid artery, and separating the internal carotid artery and the external carotid artery respectively, wherein attention is paid to avoid damaging the vagus nerve in the separation process; sequentially dissociating from the bifurcation of the common carotid artery to the head end, simultaneously ligating the proximal end of the common carotid artery on the right side to dissociate the main trunk for later use, then separating the internal and external carotid arteries on the right side, fixing the internal and external carotid arteries by a nondestructive artery clamp, making an incision near the distal end of the ligation part of the common carotid artery, rapidly inserting a suture holding plug into the incision by using a micro-forceps, and pushing the suture holding plug for 18-20mm to cause the existence of a resistance, thereby indicating that the head end of the suture plug passes through the initial part of the middle cerebral artery and blocking the source of partial blood flow of the middle artery; ligating and fixing the blood vessel at the far end of the incision to prevent the thread plug from falling off, and suturing the skin of the rat; after the rat is ischemic for 2 hours, gently pulling the remained thread head to the incision of the common carotid artery to realize the blood flow reperfusion of the middle cerebral artery; during the operation, the temperature of the rat anus is maintained between 36.5 and 37.5 ℃, and the steps of the sham operation group are the same except that no plug is inserted; and (3) judging whether the model is successfully made according to a model making success judgment standard, and respectively scoring when the rat is awake after the operation and before and after the reperfusion by referring to a Zea Long scoring standard: 0 minute: no symptoms of nerve damage; 1 minute: the left front paw cannot be fully extended; and 2, dividing: turning to the left side; and 3, dividing: when walking, the walking stick is inclined towards the left side; and 4, dividing: it is unable to walk spontaneously.
7. The method for promoting the total expression and activity of the membrane protein molecule ErbB4 according to claim 5, wherein the method for establishing the OGD/R cell damage model comprises the following steps: three-gas incubator by direct introduction of N2In a manner to accurately control CO in the incubator2And O2The concentration is increased, and sugar in a neuron culture medium is deprived, so that an environment of oxygen and sugar deficiency of cultured neurons is created, and the condition of cerebral ischemia in a body is simulated; inoculating the hippocampal neuron suspension into a cell culture dish for culture and maturation, discarding a cell culture medium in the culture dish and replacing the cell culture medium with a sugar-free culture medium; then placing in a low oxygen workstation containing 1% O2、5%CO2、94%N2Carrying out anoxic culture for 45 min; removing the culture dish from the three-gas incubator, and replacing the sugar-free culture medium with sugar-containing fineAnd placing the cell culture medium in an original cell culture box for normal culture for 0h, 6h, 12h, 18h and 36h for detection.
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| US20140056842A1 (en) * | 2012-08-21 | 2014-02-27 | Jonathan Sackner-Bernstein | Cellular therapeutic approaches to traumatic brain and spinal cord injury |
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2019
- 2019-11-14 CN CN201911114370.7A patent/CN110714068A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003099321A1 (en) * | 2002-05-24 | 2003-12-04 | Zensun (Shanghai) Sci-Tech. Ltd. | Methods for preventing, treating or delaying cardiac toxicity using neuregulin |
| WO2006108581A2 (en) * | 2005-04-15 | 2006-10-19 | Cenix Bioscience Gmbh | Human marker genes and agents for cardiovascular disorders and artherosclerosis |
| CN102389569A (en) * | 2011-11-10 | 2012-03-28 | 浙江大学 | Application of ErbB receptor agonist in preparing medicines for treating ischemic cerebrovascular diseases |
| US20140056842A1 (en) * | 2012-08-21 | 2014-02-27 | Jonathan Sackner-Bernstein | Cellular therapeutic approaches to traumatic brain and spinal cord injury |
Non-Patent Citations (1)
| Title |
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