CN116942829A - Application of membrane protein CMTM4 as drug target for treating inflammatory bowel disease and marker for monitoring UC disease progress - Google Patents
Application of membrane protein CMTM4 as drug target for treating inflammatory bowel disease and marker for monitoring UC disease progress Download PDFInfo
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Abstract
The invention provides application of a membrane protein CMTM4 or CMTM4 gene in medicines for treating inflammatory bowel diseases. The invention discovers and proves that the expression of CMTM4 is reduced along with the increase of the severity of the UC patient, and the CMTM4 has a certain protection effect on ulcerative colitis. In vivo experiments in the embodiment part of the invention prove that when Cstm 4 gene is knocked out, the weight of the mice is obviously reduced, the colon length is obviously shortened, the intestinal inflammation of the mice is obviously aggravated, inflammatory factors such as TNF-alpha, IL-1 beta and the like are obviously increased, pathological damage of tissues is obviously aggravated, the intestinal mucosa permeability is increased, the intestinal flora structure is changed, and the expression of IL-17 signal channel related molecules such as S100a8, S100a9 and the like is up-regulated.
Description
Technical Field
The invention relates to the field of medical biology, in particular to application of a membrane protein CMTM4 serving as a therapeutic target of ulcerative colitis and a marker for monitoring disease progression in medicines for treating inflammatory bowel diseases.
Background
Inflammatory bowel disease (inflammatory bowel disease, IBD) is a chronic, non-specific, inflammatory bowel disease whose etiology is not yet completely defined, and mainly includes two major categories, ulcerative colitis (ulcerative colitis, UC) and Crohn's Disease (CD). In recent years, the incidence of IBD in China is on the rise. UC is mainly characterized by epithelial injury, and lesions mainly involve colonic mucosa and submucosa, and have long disease course and are easy to relapse. Various treatment regimens, which are based on dietary intervention, 5-aminosalicylic acid formulations, corticosteroids, immunosuppressants, biological agents and surgical treatments, can only result in histological and even clinical relief for some patients, and still be unresponsive or nonresponsive to various treatments.
CMTM (CKLF-like MARVEL transmembrane domain-containing family) is a gene family that has been studied for a long time by the inventor's subject group. There have been studies suggesting that CMTM family members play an important role in a variety of tumors such as head and neck squamous cell carcinoma, colorectal cancer, lung adenocarcinoma, and the like. In 2017, nature journal publication 2, it was revealed that CMTM4 is a regulator of Programmed death ligand-1 (PD-L1) protein, which protects against lysosome-mediated degradation and increases its stability, thereby enhancing the ability of tumor cells to suppress immune responses. However, the prevention and treatment effect of CMTM4 in inflammatory bowel disease, especially ulcerative colitis, has not been studied.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the application of the membrane protein CMTM4 or CMTM4 gene in medicines for treating inflammatory bowel diseases. The invention discovers the protective effect of the membrane protein CMTM4 or CMTM4 gene on ulcerative colitis, and can be used as a new target for treating ulcerative colitis.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
in a first aspect, the invention provides the use of the membrane protein CMTM4 or CMTM4 gene in a medicament for the treatment of inflammatory bowel disease.
Further, the inflammatory bowel disease includes ulcerative colitis and crohn's disease.
Further, the CMTM4 gene is involved in ulcerative colitis via the IL-17RC-S100a 8/9-gut flora axis.
The invention discovers that the CMTM4 gene plays a role in flora regulation by reducing the expression of IL-17RC and further up-regulating S100a8/9, and further participates in ulcerative colitis.
In a second aspect, the invention provides a target for the treatment of inflammatory bowel disease, which is the membrane protein CMTM4 or CMTM4 gene.
In a third aspect, the invention provides a medicament for treating inflammatory bowel disease, the medicament comprising the membrane protein CMTM4 and pharmaceutically acceptable pharmaceutical excipients.
Further, the inflammatory bowel disease includes ulcerative colitis and crohn's disease.
In a fourth aspect, the invention provides application of a membrane protein CMTM4 or CMTM4 gene in preparing a medicine for inhibiting protein molecules related to inflammatory reaction of intestinal tracts.
Further, the inflammatory response related protein molecules include calbindin S100a8, calbindin S100a9, TNF-alpha, IL-1 beta or/and IL-17.
In a fifth aspect, the invention provides the use of the membrane protein CMTM4 or CMTM4 gene in a medicament or formulation as a marker for monitoring the progression of ulcerative colitis disease.
In a sixth aspect, the invention provides the use of the membrane protein CMTM4 or CMTM4 gene in a medicament or formulation as a target for modulating intestinal flora homeostasis.
The invention has the beneficial effects that: the invention discovers and proves that the CMTM4 gene or protein has a certain protective effect on ulcerative colitis for the first time. In vivo experiments in the embodiment part of the invention prove that when Cstm 4 gene is knocked out, the weight of the mice is obviously reduced, the colon length is obviously shortened, the intestinal inflammation of the mice is obviously aggravated, inflammatory factors such as TNF-alpha, IL-1 beta and the like are obviously increased, the pathological damage of tissues is obviously aggravated, the permeability of intestinal mucosa is increased, the intestinal flora structure is changed, and the expression of signal channel related molecules such as calbindin S100a8, S100a9, TNF-alpha, IL-1 beta, IL-17 and the like is up-regulated. The expression level of CMTM4 gene decreases with increasing severity of ulcerative colitis disease, and decreases with increasing severity of the disease. Therefore, the membrane protein CMTM4 or CMTM4 gene can be used as a new target for treating ulcerative colitis and can also play a role in monitoring the disease development. The membrane protein CMTM4 or CMTM4 gene can be used for preparing a novel medicament for treating ulcerative colitis.
Drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate the invention and together with the embodiments of the invention, serve to explain the invention. In the drawings:
FIG. 1 is a schematic representation of CMTM4 expression in an inflammatory state in a GEO database.
FIG. 2 is a schematic representation of CMTM4 expression in colon tissue of mice before and after molding.
FIG. 3 is a schematic representation of CMTM4 expression in colonic mucosa of patients with various degrees of severity UC (increasing UC severity, divided into 3 classes of light, medium and heavy; mild: cryptitis 25% or less, cryptitis 10% or less; moderate: cryptitis 25% or cryptitis 10% or small mucosal erosion foci; severe: ulcerations or multifocal erosion).
Fig. 4 is a schematic representation of a knockout of Cmtm4 exacerbating DSS-induced enteritis.
Fig. 5 is a schematic diagram showing that Cmtm4 knockout can alter intestinal flora structure.
FIG. 6 is a schematic diagram showing the inflammatory phenotype of an antibiotic-swept intestinal flora to alleviate exacerbation of Cstm 4 knockout.
FIG. 7 is a schematic representation of the consistency of Wild Type (WT) enteritis and Cmtm4 knockout enteritis murine phenotypes after caged treatment.
FIG. 8 is a schematic representation of transcriptome sequencing and validation of WT enteritis and Cmtm4 knockout enteritis murine colon tissue.
FIG. 9 is a schematic representation of phenotype analysis of Cmtm4 knockout enteritis mice and Cmtm4 knockout enteritis mice after FPS-ZM1 treatment.
Detailed Description
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1
By GEO database search, CMTM4 expression was found to be reduced in inflammatory states (fig. 1). Verification was then performed in animal models (fig. 2) and clinical cohorts (fig. 3). To explore the function of CMTM4 in inflammatory bowel disease, animal experiments were designed as follows:
the Cmtm4 knockout mice used in this example were given to the Korean professor task group of the department of medicine of Beijing university, and the construction method of Cmtm4 knockout mice is described in FuJun Liu et al mol Cell Proteomics,2019 (Integrated Analyses of Phenotype and Quantitative Proteome of CMTM4 Deficient Mice Reveal Its Association with Male Fertility). The experimental mice were divided into 4 groups in total, wherein the control group was a Wild Type (WT) group and a Cmtm4 knockout group, and the experimental group was a WT enteritis group and a Cmtm4 knockout enteritis group. Wild Type (WT) C57 mice and Cmtm4 knockout mice used in the experiments were bred for the inventors subject group protection. 3-6 male mice with the age of 8 weeks are taken from each group, and the weight is between 20 and 22 g. The drinking water of the experimental group contained 2.5% Dextran Sodium Sulfate (DSS) (MP company in the united states, CAT NO:160110,LOT NO:S5148) and was freely drunk, and after 5 days, was changed to normal animal drinking water. The control group always drinks normal animal drinking water. Body weight and hematochezia were monitored daily. Colon tissue and serum were taken by killing mice on days 8-9 of modeling. The results show that: the severity of enteritis in the Cmtm4 knockout enteritis group was heavier than that in the WT enteritis group (fig. 4). To explore the importance of gut flora in the action of CMTM4 on inflammatory bowel disease, we examined WT mice and CMTM4 -/- Changes of fecal flora before and after enteritis of mice, studies show that Cmtm4 knockout can change intestinal flora structure, such as H production 2 S bacteria increased and Akk bacteria decreased (fig. 5).
Example 2
Experiments were divided into 1 total, and 3 week old WT mice and Cmtm4 knockout mice were subjected to the same cage treatment. The experimental mice were bred for the subject group of the inventors. After 8 weeks of age, the drinking water was adjusted to 2.5% dss, and was freely drunk, and after 5 days, was changed to normal animal drinking water. Body weight and hematochezia were monitored daily. Colon tissue and serum were taken by killing mice on days 8-9 of modeling. The results show that: the severity of enteritis tended to be consistent in both groups of mice (fig. 7).
Example 3
Experiments were divided into a total of 2 groups, WT Block enteritis group and Cmtm4 knockout Block enteritis group. The experimental mice were bred for the subject group of the inventors. 3-6 male mice with the age of 8 weeks are taken from each group, and the weight is between 20 and 22 g. Two groups of mice were first given drinking water containing the tetrad antibiotic and were freely drunk, 28 days later, replaced with drinking water containing 2.5% dss, and 5 days later, replaced with drinking water for normal animals. Body weight and hematochezia were monitored twice weekly. Colon tissue and serum were taken from the mice at day 36-37 of molding. The results show that: after removal of the intestinal flora, the phenotype of exacerbating enteritis by cm tm4 knockout was partially reversed (fig. 6).
Example 4
The experiments were divided into a total of 2 groups, WT RAGE Block enteritis group and Cmtm4 knockout RAGE Block enteritis group. The experimental mice were bred for the subject group of the inventors. 3-6 male mice with the age of 8 weeks are taken from each group, and the weight is between 20 and 22 g. Two groups of mice were given 2.5% dss in drinking water, which was freely consumed for 5 days before being replaced with normal animal drinking water. The mice were intraperitoneally injected with FPS-ZM1 (RAGE blocker,1 mg/kg) daily during the experiment. Body weight and hematochezia were monitored daily. Colon tissue and serum were taken by killing mice on days 8-9 of modeling. The results show that: the severity of enteritis tended to be consistent in both groups of mice (fig. 9).
In summary, the inventors found that CMTM4 expression was reduced in inflammatory states by GEO database search (fig. 1). Subsequently, the inventors have validated in animal models and clinical cohorts and found that as the degree of inflammation increases, the expression level of CMTM4 decreases (fig. 2 and 3).
The above experiments demonstrate that knockout of Cmtm4 increases susceptibility of mice to Dextran Sodium Sulfate (DSS) induced enteritis (fig. 4). After removal of intestinal flora with four antibiotics, cstm 4 was found -/- The phenotype of mice-susceptible DSS induced enteritis was partially reversed (fig. 6). Thus, the invention considers that the pathogenic part of CMTM4 involved in UC/CD depends on intestinal flora and can be used as a potential target for regulating the steady state of the intestinal flora.
Based on the above results, the invention finds that the expression amount of CMTM4 protein has correlation with the severity of UC, and finds that knockout of Cstm 4 increases susceptibility of mice to DSS induced enteritis, and reduces survival rate. Thus, the present invention developed a new target for treating UC and monitoring disease progression.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
1. Use of the membrane protein CMTM4 or CMTM4 gene in a medicament for the treatment of inflammatory bowel disease.
2. The use of claim 1, wherein the inflammatory bowel disease comprises ulcerative colitis and crohn's disease.
3. The use according to claim 1 or 2, wherein the CMTM4 gene is involved in ulcerative colitis via the IL-17RC-S100a 8/9-gut flora axis.
4. A target for treating inflammatory bowel disease, wherein the target is membrane protein CMTM4 or CMTM4 gene.
5. A medicament for treating inflammatory bowel disease, which is characterized by comprising membrane protein CMTM4 and pharmaceutically acceptable pharmaceutical excipients.
6. The medicament of claim 5, wherein the inflammatory bowel disease comprises ulcerative colitis and crohn's disease.
7. The application of membrane protein CMTM4 or CMTM4 gene in preparing protein molecule medicine for inhibiting intestinal inflammatory reaction.
8. The use according to claim 7, wherein the inflammatory response-related protein molecules comprise calbindin S100a8, calbindin S100a9, TNF- α, IL-1 β or/and IL-17.
9. Use of the membrane protein CMTM4 or CMTM4 gene in a medicament or formulation as a marker for monitoring the progression of ulcerative colitis disease.
10. Use of the membrane protein CMTM4 or CMTM4 gene in a medicament or formulation as a target for regulating intestinal flora homeostasis.
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