KR101854962B1 - Pharmaceutical composition for preventing or treating neurodegenerative diseases comprising inducer or activator of CRTC3 - Google Patents
Pharmaceutical composition for preventing or treating neurodegenerative diseases comprising inducer or activator of CRTC3 Download PDFInfo
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- KR101854962B1 KR101854962B1 KR1020150135502A KR20150135502A KR101854962B1 KR 101854962 B1 KR101854962 B1 KR 101854962B1 KR 1020150135502 A KR1020150135502 A KR 1020150135502A KR 20150135502 A KR20150135502 A KR 20150135502A KR 101854962 B1 KR101854962 B1 KR 101854962B1
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- 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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Abstract
The present invention relates to a pharmaceutical composition for the prevention or treatment of cranial nerve diseases containing CRTC3 expression promoter or activator as an active ingredient and a method for screening the same. More particularly, the present invention relates to a pharmaceutical composition for preventing or treating cranial nerve disease, And CRTC3 is used as a marker composition for the diagnosis of neurological diseases as a result of confirming reactive astrocytosis in brain tissue in brain tissue of CRTC3-deficient animal model, and a composition containing CRTC3 expression promoter or activator as an active ingredient can be used as a marker for cranial nerve A method for screening a pharmaceutical composition for treating a cranial nerve disease by providing a pharmaceutical composition for treating a disease and confirming the promotion or activity level of CRTC3 expression can be provided.
Description
The present invention relates to a pharmaceutical composition for the prevention or treatment of cranial nerve diseases containing CRTC3 expression promoting agent or activator as an active ingredient, and a screening method therefor.
cAMP response element binding protein (CREB) is a factor that binds to a specific DNA sequence and controls the transcription of several genes. Activated CREB binds to the CRE region and binds to CBP (CREB binding protein) It is an intracellular factor that is important for cell proliferation, differentiation and survival by regulating the activity of a specific gene through invocation.
These CREBs are associated with various functions in the brain such as memory, development, survival of cells, and internal clock, and 4,000 genes are known to be regulated by CREB. However, it has not yet been elucidated how each region of the brain can only read a specific gene group to express a site-specific function.
Currently, many CREB binding proteins such as STAT, TCF3, P53, and SREBF have been reported. These binding proteins interact with CREB to activate various gene transcription, thereby regulating cell proliferation and differentiation to control biological functions . Among them, cAMP-regulated transcriptional co-activators TORC1 (CRTC1) and TORC2 (CRTC2) are CREB binding proteins that regulate the expression of CREB. In recent reports, CRTC2 interacted with CREB (Coactivator CRTC2, hepatic ER stress and fasting gluconeogenesis, 2009). However, the function of CRTC3 and CREB in brain has not yet been reported.
The present invention is to provide a marker composition for diagnosing cerebral neuropathy comprising CRTC3 as an active ingredient, a pharmaceutical composition for treating a cranial nerve disease containing the CRTC3 expression promoting or activating agent as an active ingredient, and a method for screening a pharmaceutical composition for treating a cranial nerve disease.
The present invention provides a biomarker composition for the diagnosis of brain disease comprising CRTC3 (cAMP-regulated transcriptional co-activators 3).
The present invention provides a kit for diagnosing cerebral nerve disease comprising an agent for detecting CRTC3 (cAMP-regulated transcriptional co-activators 3).
The present invention provides a pharmaceutical composition for the prevention or treatment of cerebral nerve diseases, which comprises as an active ingredient CRTC3 (cAMP-regulated transcriptional co-activators 3) expression promoting agent or activator.
The present invention provides a method of treating a CRTC3 deficient animal model comprising: Measuring CRTC3 expression or activation level in a CRTC3 deficient animal model treated with the test substance; And selecting a test substance having increased CRTC3 expression or activation level as compared with a control sample.
According to the present invention, CRTC3 expression is decreased in brain tissue of a patient with Alzheimer's dementia, which is a brain disease, and reactive astrocytosis of cerebral tissue in a brain tissue of a CRTC3-deficient animal model is confirmed. Thus, CRTC3 is used as a marker composition And a composition containing the CRTC3 expression promoting or activating agent as an active ingredient can be used as a pharmaceutical composition for treating a brain disease and a method for screening a pharmaceutical composition for treating a brain nerve disease by confirming the promotion or activity level of CRTC3 expression .
FIG. 1 is a Western blot result showing the level of CRTC3 expression in brain tissues of Alzheimer's patients and normal group.
Figure 2 shows the results of GFAP staining confirming the activation level of reactive astrocytes in the brain tissue of an animal model of CRTC3 deficient mice.
FIG. 3 shows the result of treating CRTC2 and CRTC3 alone or in the presence of capsaicin, and confirming the expression level of EVA-1, a target gene for CREB.
The present invention provides a biomarker composition for the diagnosis of brain disease comprising CRTC3 (cAMP-regulated transcriptional co-activators 3).
The present invention provides a kit for diagnosing cerebral nerve disease comprising an agent for detecting CRTC3 (cAMP-regulated transcriptional co-activators 3).
According to one embodiment of the present invention, Western blotting was performed using brain samples from Alzheimer's dementia (AD) patients and normal aged subjects and whole brain tissue obtained from APP / PS1 mice to determine the expression level of CRTC3. The level of CRTC3 expression was significantly decreased in Alzheimer's patients compared to the normal group.
In addition, as shown in FIG. 2, when CRTC3 deficiency was observed in the brain tissue of a mouse model of CRTC3-deficient mice, reactive astrocytosis, in which astrocytic cells showed excessive activation, I could confirm.
From the above results, it can be confirmed that CRTC3 can play a role in regulating the activity of astrocytes and that the decrease in expression of CRTC3 acts as a pathogenesis of neuronal diseases such as Alzheimer's disease.
Accordingly, the present invention can provide a pharmaceutical composition for the prevention or treatment of cerebral nerve disease, which contains CRTC3 expression promoter or activator as an active ingredient.
The CRTC3 expression promoter or activator may increase CRTC3 expression or activity in brain tissue, thereby reducing astrocyte activity and increasing CREB expression.
The CRTC3 expression promoter or activator may be any one selected from the group consisting of compounds, peptides, aptamers, and antibodies that increase CRTC3 expression or activity in brain tissue.
The cranial nerve disease may be selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Niemann's disease and stroke.
According to another embodiment of the present invention, CRTC3 and CRTC2 were treated and the level of expression of EVX-1, a target gene of CREB, was confirmed in order to confirm whether CRTC3 can regulate CREB expression. As a result, as shown in Fig. 3, the expression level of EVX-1 was higher in the CRTC3-treated experimental group than in the CRTC2-treated experimental group.
From the above results, it was confirmed that as the activity of CRTC3 increases, CREB expression level increases.
The CRTC3 expression promoting agent or activator may be contained in an amount of 0.01 to 10 parts by weight based on 100 parts by weight of the total pharmaceutical composition.
In one embodiment of the present invention, the pharmaceutical composition for the prevention or treatment of cerebral nerve disease containing the CRTC3 expression promoting agent or the activator as an active ingredient may be administered orally, parenterally, Gels, suspensions, emulsions, drops, or liquid preparations may be used.
In another embodiment of the present invention, the pharmaceutical composition for the prevention or treatment of cerebral nerve diseases containing the CRTC3 expression promoting agent or the activator as an active ingredient may be formulated with appropriate carriers, excipients, disintegrants, sweeteners, A lubricant, a lubricant, a flavoring agent, an antioxidant, a buffer, a bacteriostatic agent, a diluent, a dispersant, a surfactant, a binder and a lubricant.
Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.
According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.
The preferred dosage of the pharmaceutical composition according to the present invention may vary depending on the condition and body weight of the subject, the kind and degree of the disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.
In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.
The present invention provides a method of treating a CRTC3 deficient animal model or a cell; Measuring the level of CRTC3 expression or activation in the CRTC3 deficient animal model or cells treated with the test substance; And selecting a test substance having increased CRTC3 expression or activation level as compared with a control sample.
The CRTC3 expression or activation level can be confirmed by the expression of EVX-1, which is a target gene for CREB.
The CRTC3 expression or activation level was determined by RT-PCR, ELISA, immunohistochemistry, Western blotting and flow cytometry (FACS). And can be measured in any one selected from the group consisting of.
According to another embodiment of the present invention, the capsaicin reported to exhibit the therapeutic effect of Alzheimer's may enhance the activity of CRTC3. As a result, it was found that treatment of 293T cells with capsaicin and CRTC3 as shown in Fig. 3, 1 expression, the expression level of EVX-1 was significantly higher in the experimental group treated with capsaicin and CRTC3 than in the group treated with CRTC3 alone as shown in FIG.
From the above results, it was confirmed that capsaicin is a substance activating CRTC3, and it was confirmed that CRTC3 was activated and showed the therapeutic effect of Alzheimer.
The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.
< Example 1> In patients with Alzheimer's dementia Of CRTC3 Identify expression levels
Expression levels of CRTC3 were confirmed in brain samples from Alzheimer 's dementia (AD) and normal aged subjects.
As shown in Table 1, seven medial temporal gyri from eight AD patients and seven age- and gender-matched controls were obtained from the Netherlands Brain Bank.
The pathological staging of AD was based on the Braak staging system (Braak & Braak 1991).
Western blotting was also performed using whole brain tissues from control mice and APP / PS1 mice of the same age (12 months) to confirm the expression level of CRTC3.
A mouse or human brain tissue lysate was prepared using a protein extraction solution (Pro-Prep, Intron).
Proteins were separated by SDS-PAGE, transferred to a polyvinylidene difluoride membrane (PVDF membrane, Bio-Rad), and washed with TTBS (Tween 20-Tris-Buffered Saline) buffer containing 5% skim milk Respectively.
The blocked membranes were incubated with antibodies to CRTC3 (1: 1000, Cell Signaling) and β-actin (β-actin, 1: 1000, Sigma) for 16 h at 4 ° C.
The membrane was then washed with TTBS buffer, incubated with the secondary antibody for 1 hour at 23 ° C, and visualized with enhanced chemiluminescence reagents (Thermo).
As a result, as shown in Fig. 1, the level of CRTC3 expression was significantly reduced in Alzheimer's patients compared to the normal group.
From the above results, it can be suggested that CRTC3 can protect the cranial nerve.
* PMD (postmortem delay): post-mortem delay
< Example 2> CRTC3 Identification of brain tissue changes due to deficiency
The brain tissue of CRTC3 - deficient mouse animal model was stained with GFAP and reactive astrocytosis, a characteristic pathologic finding of cranial nerve disease, was identified.
One. CRTC3 Production of deficient mouse animal models
A neomycin cassette was inserted into the N-terminal domain (Exon1) of Crtc3 encoding CBD, which plays an important role in binding to CREB, and a structure in which both genomic DNAs of Crtc3 exon1 were used as an arm was subjected to electroporation to ES cells After the neomycin selection, the surviving cells were identified by genomic DNA PCR and southern blot. Targeted cells were found and injected into pregnant mice to construct Chimera mice.
Through crosses, heterozygous mice were constructed by locating the mice into which the targeting vector had entered the germ cells.
After that, heterozygous mice were crossed to construct a homozygous CRTC3 KO mouse (Nature. 2010 Dec 16; 468 (7326): 933-9.Doi: 10.1038 / nature09564.RCTC3 links catecholamine signaling to energy balance).
2. Identification of astrocyte activity by immunohistochemical staining
Brains of CRTC3 knockout and wild-type mice were excised and fixed in 4% paraformaldehyde (0.1 M PB pH 7.4) for 36 hours. The fixative was washed away with running water and dehydrated with 70, 80, 90 and 100% ethanol and dipped twice in 100% xylene to make it transparent.
Then, it was immersed in paraffin dissolved at 60 캜.
The paraffin embedded tissues were cut to a thickness of 4 mu m and adhered to the coating slides. The tissues were deparaffinized with 100% xylene and again functionalized with 100, 90, 80 and 70% ethanol. The cells were washed with distilled water and treated with PBS buffer containing 2% normal serum, 2% bovine serum albumin (BSA) and 0.1% Triton X-100 for 30 minutes to remove non-specific reactions. So that they can pass.
Cells were then treated with GFAP (1: 300, Sigma) and CRTC3 (1: 300, Abcam) primary antibody diluted to appropriate concentrations in PBS buffer containing 2% normal horse serum and 2% bovine serum albumin The reaction was allowed to proceed overnight at 4 ° C.
Then, the cells were washed three times with PBS for 5 minutes each, and the secondary antibody solution with Cy3 (red) or FITC (green) was reacted at room temperature for 1 hour, washed three times for 5 minutes with PBS, and attached with cover glass .
As a result, as shown in Fig. 2, astrocytes were overactivated in the brain tissue of a mouse animal model deficient in CRTC3 as compared with brain tissue of normal mice.
From the above results, it was confirmed that CRTC3 can play a role in regulating the activity of astrocytes, and that the decrease in the expression of CRTC3 can act as a pathogenesis of brain diseases such as Alzheimer's disease.
< Example 3> On CRTC3 by CREB Confirmation of increased expression
In order to confirm the CREB expression control effect of CRTC3, the expression level of the target gene of CREB according to CRTC3 and CRTC2, EVX-1, was confirmed.
In addition, capsaicin (Capsaicin), which has been shown to be effective in treating Alzheimer's disease, was treated together to confirm the effect of increasing the activity of CRTC3.
The expression of luciferase (luciferase) was regulated in 293T cells (ATCC) according to the EVX-1 promoter activity by ligating fly luciferase to the promoter of CREB target gene, EVX-1.
To confirm the association with CRTC3, expression of luciferase was compared between CRTC3 expressing cells and unexpressed cells with forskolin. Twenty five ng CRTC2 and CRTC3 were transfected, and capsaicin (1 μM) The pretreatment was carried out 1 hour before the treatment with phoscholine, and the effects of CRTC2, CRTC3 and capsaicin were compared.
The β-galactosidase construct, which is regulated by β-actin, was simultaneously expressed and standardized for transfection and normalization of cell numbers.
As a result, as shown in FIG. 3, higher expression level of EVX-1 was observed in the CRTC3-treated experimental group than in the CRTC2-treated experimental group, and EVX-1 expression was significantly decreased in the experimental group treated with capsaicin and CRTC3 It was confirmed to be a very high level.
From the above results, it was confirmed that as the activity of CRTC3 increases, the level of CREB expression increases. Capsaicin activates CRTC3 and thus has an effect on treating Alzheimer's disease.
While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.
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