CN115154587A - Application of Creld2 protein or gene in prevention and treatment of intestinal injury - Google Patents
Application of Creld2 protein or gene in prevention and treatment of intestinal injury Download PDFInfo
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- CN115154587A CN115154587A CN202210612380.9A CN202210612380A CN115154587A CN 115154587 A CN115154587 A CN 115154587A CN 202210612380 A CN202210612380 A CN 202210612380A CN 115154587 A CN115154587 A CN 115154587A
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Abstract
The invention relates to the fields of molecular biology and biomedicine, and particularly discloses application of Creld2 protein or gene in prevention and treatment of intestinal injury. Based on a mouse intestinal radioactive injury model, results show that Creld2 deficiency can aggravate signs, gross morphology, tissue morphology, apoptosis, proliferation inhibition and repair inhibition of intestinal injury, so that weight loss is more obvious, and death of animals is accelerated, therefore, endogenous Creld2 has a protective effect and can resist intestinal injury caused by injury stimulation. The result shows that the small intestine organoid lacking Creld2 can aggravate the damage degree and inhibit the damage repair process, and the result further proves that endogenous Creld2 has a protective effect and can resist the intestinal damage caused by the injury stimulation.
Description
Technical Field
The invention relates to the fields of molecular biology and biomedicine, in particular to application of Creld2 protein or gene in preventing and treating intestinal injury.
Background
CRELD2 is a cysteine-rich epidermal growth factor-like domain, and belongs to a novel secreted protein in Epidermal Growth Factor (EGF) superfamily that is homologous to CRELD 1. The CRELD2 gene is recognized for the earliest reason that the gene participates in the regulation of endoplasmic reticulum stress, namely, the endoplasmic reticulum stress signal transduction response and the unfolded protein response; and are involved in the intracellular transport of the alpha 4 and beta 2 subunits of acetylcholine receptors. In bone marrow mesenchymal stem cells, CRELD2 has the effects of enhancing bone morphogenetic protein-9-induced osteogenesis and matrix mineralization, and plays a fundamental role in cartilage development by combining with cartilage matrix protein-3. In addition, CRELD2 is a paracrine factor of tumor-associated fibroblasts in a PERK-ROCK pathway and participates in the formation of a tumor microenvironment; there are also studies that suggest CRELD2 plays an important role in the maintenance and regulation of hepatic metabolic homeostasis. In addition, CRELD2 has potential as a biomarker for diagnosis of artificial joint infection and early prediction of acute kidney injury after surgery.
At present, few reports about the functional research of the Creld2 protein and gene are reported, and particularly, no report exists about the relationship between the protein and the gene and intestinal tract injury. Therefore, the exploration of new application of the Creld2 protein and the gene is helpful for the research of the occurrence and development mechanism of related diseases and the development of therapeutic drugs.
Radiotherapy is widely used to treat malignant tumors, but its side effects are also very significant. The high radiosensitivity of the intestine and its location in the abdominal cavity make the small intestine one of the most severely damaged organs during radiation therapy. According to the pathological stage, the radioactive intestinal injury can be divided into acute and chronic, the former occurs within 3 months of radiotherapy and is often accompanied with digestive tract symptoms, such as nausea, vomiting, inappetence, bloody stool and the like. While chronic radiation injury of the intestine occurs after 3 months, most of the chronic radiation injury of the intestine is developed from acute disease and is clinically manifested as abdominal pain, and because the intestinal mucosa is damaged, pathogens such as bacteria and the like flow into the whole body to cause septicemia and even death. After irradiation, intestinal epithelial cells and vascular endothelial cells are damaged, the proliferation capacity of intestinal crypt cells is limited, and inflammatory edema, cell necrosis and even fibrosis are caused. Although the use of antibiotics, hydration and support therapy of bone marrow transplantation can avoid death due to hematopoietic syndromes, there is no approved therapy for protecting or alleviating radiation-induced bowel damage, and thus the development of new therapeutic drugs for radiation-induced intestinal damage is of great importance. The application of the Creld2 protein or gene in preventing and treating intestinal injury is researched by taking radioactive intestinal injury as an example.
Disclosure of Invention
The invention aims to provide the application of the Creld2 protein or gene in preventing and treating intestinal injury aiming at the defects in the prior art.
The invention provides a use of Creld2 protein or gene and a synergist thereof in preparing a medicament for preventing and treating intestinal injury.
The synergist is selected from an agonist, an up-regulator or a stabilizer, and the intestinal injury refers to intestinal injury caused by stimulation such as radiation.
In a second aspect of the invention, the use of the Creld2 protein or gene and the synergist thereof is provided for preparing a food for preventing intestinal injury.
The synergist is selected from an agonist, an up-regulator or a stabilizer, and the intestinal injury refers to intestinal injury caused by stimulation such as radiation.
In a third aspect of the invention, there is provided the use of a Creld2 protein or gene and a synergist thereof in the preparation of a medicament for:
1) Improving weight loss caused by intestinal radiation injury; or
2) The death caused by the radioactive damage of the intestinal tract is delayed; or
3) Improving the shortening of the small intestine length and the whole intestinal tract length caused by the radioactive damage of the intestinal tract; or
4) Improving intestinal villus and crypt injury caused by intestinal radioactive injury; or
5) Reducing intestinal tissue cell apoptosis caused by intestinal radiation injury; or
6) Promoting the proliferation of intestinal tissue stem cells after the intestinal radiation injury; or
7) Improve the defect of crypt cells caused by intestinal radioactive injury.
The synergist is selected from an agonist, an up-regulator or a stabilizer.
In a fourth aspect of the invention, there is provided the use of the Creld2 protein or gene and its potentiator for:
1) Preparing an agent for improving the radioactive damage degree of the small intestine organoid; or
2) Preparing a reagent for promoting the repair of the radiation damage of the small intestine organoid.
The synergist is selected from an agonist, an up-regulator or a stabilizer.
In a fifth aspect of the present invention, there is provided a method for screening a substance for treating or ameliorating radioactive damage to the intestinal tract of an individual, comprising the steps of:
a) Contacting the candidate substance with a system comprising a Creld2 protein or gene,
b) And observing the influence of the candidate substance on the Creld2 protein or gene expression and activity, wherein if the candidate substance can promote the Creld2 gene expression or improve the Creld2 protein activity, the candidate substance is a potential substance for treating or improving the intestinal radioactive injury of the individual.
The sixth aspect of the invention provides the use of the Creld2 protein or gene and the synergist thereof in preparing a reagent for treating or improving intestinal injuries such as radioactivity and the like.
The synergist is selected from an agonist, an up-regulator or a stabilizer.
The invention constructs a Creld2 deficient gene knockout mouse (Creld 2) based on a LoxP-Cre system -/- ) (ii) a The mouse breeding process and the obtained target mouse are proved to be correct by carrying out genotype identification on a plurality of tool mice used in the breeding process and the obtained offspring target mouse and carrying out knockout verification on the gene and protein levels by a plurality of methods, namely Creld2 -/- The mouse was successfully constructed. Further, by examining Creld2 -/- General conditions and basic phenotypes of mice, includingThe results of the indicators of the appearance signs, the genotype distribution, the weight change, the long-term survival, the tissue structure and the like of the mice show that the knockout of the Creld2 gene has no obvious influence on the embryonic development, the growth process, the tissue structure and the like of the mice, namely the deletion of the Creld2 gene has no obvious influence on the basic phenotype, the growth and the like of the mice.
The invention utilizes a littermate contrast wild type mouse and a Creld2 deficient gene knockout mouse to prepare a mouse intestinal radioactive damage model by adopting a method of local irradiation of an abdomen. Studies show that compared with wild mice in which Creld2 exists, creld2 deficiency can aggravate the signs of intestinal injury, gross morphology, tissue morphology, apoptosis, proliferation inhibition and repair inhibition, so that the weight loss is more obvious, and the death of animals is accelerated. These results suggest that endogenous Creld2 itself has a protective effect against the intestinal damage caused by noxious stimuli.
The invention relates to a C57 mouse and Creld2 +/+ Mouse, creld2 -/- Separating a mouse to obtain a small intestine crypt, in vitro culturing to obtain a corresponding small intestine organoid, and adopting the small intestine organoid to radiate to prepare an ex vivo small intestine organoid radioactive injury model. Studies have shown that small intestinal organoids deficient in Creld2 may exacerbate the extent of injury, inhibit the progress of injury repair, etc., as compared to small intestinal organoids present in Creld 2. These results further demonstrate that endogenous Creld2 has a protective effect against the intestinal damage caused by noxious stimuli.
Drawings
FIG. 1.Creld2 deficient Whole body knockout mice (Creld 2) -/- ) Cultivating flow chart.
Figure 2.Creld2 -/- The result of mouse genotype identification is shown schematically. M: represents Marker; band 1 is 234bp and Creld2 +/+ The genotype; stripe 2 is 343bp +234bp, representing Creld2 +/- The genotype; the band 3 is 343bp and represents Creld2 -/- The genotype of the plant.
FIG. 3 shows the knockout of Creld2 mRNA in mouse tissues. The data are Mean + -SEM, *** P<0.001。
figure 4 knock-out of creld2 protein in various tissues of mice.
FIG. 5 Creld2 knockdown in mouse serum. Creld2 Elisa test standard curve; creld2 +/+ Mice and Creld2 -/- And detecting the result of Creld2 level in the serum of the mouse. Data are Mean ± SEM.
FIG. 6.Creld2 +/- Genotype distribution of mouse selfing breeding progeny.
FIG. 7.Creld2 -/- Growth and development of the mice. A.1 age in days; b.3 days old; c.6 days old; d.3 week old; e.7 weeks old; f.19 weeks old.
FIG. 8 Creld2 of different ages of week -/- Body weight of mice changed. A. Female mouse body weight change curve; B. male mice body weight change curves. Data are Mean ± SEM, with no statistical difference in NS.
Figure 9.Creld2 -/- Long-term survival of mice. The NS was not statistically different.
Figure 10.Creld2 -/- Morphological structure of mouse tissues.
Figure 11 signs of intestinal radiation damage are more evident in creld2 deficient mice. A1-A2. Anal hemorrhage; B1-B2. Diarrhea; C1-C2. Mucous bloody stool.
Figure 12.Creld2 deficiency aggravates weight loss and death from intestinal radiation injury in mice. A. Body weight change curve (rate of decrease); B. survival curves. The data are Mean + -SEM, * P<0.05， ** P<0.01。
figure 13.Creld2 deficient mice have more severe intestinal radiation damage as generally observed.
Figure 14 the decrease in small intestine length and total intestinal length following radiation injury to the gut in creld2 deficient mice is more evident. A. The total length of the intestinal tract at different time points after molding; B. changes in length of different segments of the intestine; C. schematic representation of intestinal tract segmentation of mice. The data are Mean + -SEM, * P<0.05， ** P<0.01.WI represents the total intestinal length and SI represents the length of the small intestine.
Figure 15 intestinal villus length and intestinal crypt depth were less after radiation injury to the gut in creld2 deficient mice. A. Intestinal canal structure forms at different time points after modeling; B. length of intestinal villi; C. the depth of the crypt. The data are Mean + -SEM, * P<0.05， ** P<0.01,NS is not statistically different.
Figure 16.Creld2 deficiency exacerbates apoptosis of intestinal radiation-damaged cells. A. Typical representative images for TUNEL fluorescent staining of each group; B. and (4) carrying out quantitative statistics on the fluorescence intensity of each group. The data are Mean + -SEM, ** P<0.01。
figure 17.Creld2 deficiency aggravates inhibition of cell proliferation by intestinal radiation injury. Representative image of Ki67 immunofluorescent staining; B. and (4) carrying out quantitative statistics on fluorescence intensity of each group. The data are Mean + -SEM, * P<0.05。
figure 18.Creld2 deficiency aggravates the inhibition of intestinal crypt regeneration by intestinal radiation injury. Representative picture of Ki67 immunohistochemical staining; B. ki67 in each group of crypts + And (6) quantitatively counting the number of positive cells. The data are Mean + -SEM, ** P<0.01。
figure 19.Creld2 deficiency exacerbates the extent of small bowel organoid radiation damage. A. Observing under the mirror after each group of small intestine organoids are molded; LDH release detection to evaluate damage degree; caspase 3 activity assay to assess the extent of injury. The data are Mean + -SEM, * P<0.05， ** P<0.01。
figure 20.Creld2 deficiency exacerbates the inhibitory effect on small intestine organoid radiation damage repair. A. Performing under-mirror observation on each group of small intestine organoids for repairing radiation damage; B. average surface area of each group of small intestine organoids during the injury repair period; C. sprouting of small intestine organoids in each group during injury repair. The data are Mean + -SEM, * P<0.05， ** P<0.01。
Detailed Description
The present invention will be further described with reference to the following embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the disclosure of the present invention, and equivalents fall within the scope of the appended claims.
Creld2 protein and gene
The Creld2 protein used herein may be naturally occurring, e.g.it may be isolated and purified from a mammal. In addition, the Creld2 protein may also be artificially prepared, for example, according to conventional genetic engineering techniques. Any suitable Creld2 protein may be suitable for use in the present invention. The Creld2 protein includes the full-length Creld2 protein or a biologically active fragment thereof. As a specific embodiment, the amino acid sequence of Creld2 is basically the same as the amino acid sequence shown in SEQ ID NO. 1-2.
The amino acid sequence of the Creld2 protein formed by substitution, deletion or addition of one or more amino acid residues is also included in the invention. The Creld2 protein or a biologically active fragment thereof comprises a substituted sequence of a portion of conserved amino acids, which does not affect its activity or retains a portion of its activity. Appropriate substitutions of amino acids are well known in the art and can be readily made and ensure that the biological activity of the known molecule is not altered. These techniques allow one of skill in the art to recognize that, in general, changing a single amino acid in a nonessential amino acid region of a polypeptide does not alter biological activity.
Any biologically active fragment of the Creld2 protein may be used in the present invention. Herein, a biologically active fragment of the Creld2 protein is meant to refer to a polypeptide which still retains all or part of the function of the full-length Creld2 protein. Typically, the biologically active fragment retains at least 50%, 60% to 99% or 100% of the activity of the full length Creld2 protein.
The present invention may also employ modified or improved Creld2 proteins having all or part of their amino acids, e.g., creld2 proteins that may be modified or improved to promote half-life, efficiency, metabolism, and/or potency of the protein. The modified or improved Creld2 protein may be a conjugate of the Creld2 protein, or it may be a substituted or artificial amino acid. The modified or improved Creld2 protein or gene can have a certain difference with the natural Creld2 protein or gene, but also has the functions of the invention, and does not bring other adverse reactions or toxicity. That is, any variant that does not affect the biological activity of the Creld2 protein or the biological function of the gene may be used in the present invention.
Creld2 synergist and application thereof
The 'Creld 2 synergist' comprises an agonist, an up-regulator, a stabilizer and the like, and refers to any substance which can improve the activity of Creld2, improve the stability of Creld2, up-regulate the expression of Creld2 and prolong the effective action time of Creld2, and the substances can be used for the invention. They may be chemical compounds, small chemical molecules, biological molecules, etc. The biological molecules can be at the nucleic acid level (including DNA and RNA) and at the protein level, and can also be virus products for up-regulating Creld2 expression, and the like.
Example 1 Creld2 LoxP/LoxP Preparation of mice and Creld2 deficient knockout mice
1 Experimental method
Designing a gene targeting strategy, knocking out exons 3, 4 and 5 of the Creld2 gene as deleted functional domains, and culturing to obtain Creld2 LoxP/LoxP Mice and expanded breeding; creld2 LoxP/LoxP The mice were mated with Ella-Cre mice, and Ella-Cre background was removed in combination with C57BL/6 mice to obtain a Creld2 heterozygote (Creld 2) +/- ) A mouse; creld2 +/- Mice were selfed to obtain a full-body knockout of Creld2 deficiency (Creld 2) -/- ) Target mouse, creld2 littermate wild-type control (Creld 2) +/+ ) Mouse and Creld2 +/- Heterozygote mice (figure 1). Creld2 LoxP/LoxP In addition to the above, the mice can be used for preparing whole-body Creld2 knockout mice, and can be mated with Cre mice controlled by cell-specific promoters to prepare various cell-specific Creld2 knockout mice.
2 results of the experiment
(1) Genotyping
By systemic knockout of Creld2 deficiency (Creld 2) -/- ) Mouse, creld2 littermate wild-type control (Creld 2) +/+ ) Mouse and Creld2 +/- The tail of the mouse is clipped to extract the genomic DNA of the rat tail for PCR amplification, and the genotype identification result is shown in figure 2. And (3) analyzing electrophoresis results of PCR products: creld2 -/- The mouse has a unique band at 343 bp; creld2 +/+ Mice at 234bpHas a unique strip; creld2 +/- Mice had bands at both positions. Identified and defined Creld2 by genotype -/- Purpose mouse and Creld2 +/+ Littermates wild type mice were used to develop experimental studies; creld2 +/- Mice were used for expansion breeding to obtain the desired mice for the experiment and littermate wild type control mice.
(2) mRNA and protein level identification
For Creld2 -/- Verifying the knockout condition of Creld2 mRNA in each tissue of a target mouse by adopting real time-PCR; verifying whether the Creld2 protein in each tissue cell is knocked out through immunohistochemistry; the level of Creld2 in serum was determined using the Elisa method. The Real time-PCR result shows that Creld2 -/- The relative expression quantity of Creld2 mRNA in each tissue of the mouse is far lower than that of Creld2 +/+ Mice (fig. 3); the immunohistochemical results show that isotype IgG from primary antibody is used as negative control, compared with Creld2 +/+ Mouse, creld2 -/- The expression of the Creld2 protein in various tissues of the liver, the kidney, the stomach, the intestinal tract, the aorta, the heart, the pancreas, the lung and the like of a mouse can not be detected almost, which indicates that the Creld2 protein can not be expressed -/- Creld2 was successfully knocked out in mouse tissues (FIG. 4); elisa test results show that the littermate wild type contrast Creld2 +/+ The concentration of Creld2 in the serum of mice is at a normal level, whereas Creld2 is present in the serum of mice -/- The concentration of Creld2 in the serum of the mouse is lower than the detection lower limit value of the Elisa kit, which indicates that Creld2 is lower than the detection lower limit value of the Elisa kit -/- Creld2 in serum has been successfully knocked out in mice (FIG. 5). The above results show that Creld2 -/- The mice realize the knockout of the Creld2 gene, namely, creld2 -/- The mouse model is successfully constructed.
(3) Basic phenotype survey
Using 8-15 weeks old Creld2 +/- The mice are bred by selfing, and the distribution condition of each genotype in offspring mice is recorded and counted. As shown in FIG. 6, 21 Creld2 cells were formed +/- A total of 165 offspring mice, creld2, born to female mice in 26 litters -/- 32 mice, creld2 +/- 92 mice, creld2 +/+ Mouse 41, i.e. the distribution ratio for each genotype is 32 ≈ 1The Del's law of inheritance indicates that the knockout of the Creld2 gene has no lethal effect on the embryonic development of the mice.
In order to determine the influence of the Creld2 deletion on the general conditions of the growth and development of the mice and the like, indexes such as hair, appearance, weight change of different weeks of age and the like in the growth and development process of the mice are selected for observation and recording, and after statistical analysis, the indexes are used as the evaluation Creld2 -/- General indicators of mouse growth and development. Creld2 is added +/- Marking newborn progeny mice obtained by selfing propagation of the mice, weighing every week from the 1 st week of birth, observing the appearances of the newborn progeny mice, breeding the newborn progeny mice in cages for 4 weeks old, identifying the genotypes of the newborn progeny mice, and enabling the obtained genotypes and sex information to correspond to the previous period marks; and observing and recording the growth condition of the mice until the mice are 8 weeks old, photographing the growth condition of the mice and drawing a weight change curve. FIG. 7 shows Creld2 -/- The growth and development process of the mice is as follows: a:1 day old, B:3 days old, C:6 days old, D:3 weeks old, E:7 weeks old, F:19 weeks old. Creld2 -/- The appearance of the hair of the mice in the growth and development process is not obviously abnormal, and abnormal physical characteristics are not observed. The results of the body weight changes are shown in FIG. 8, and the left and right are the body weight change curves of female mice and male mice, respectively, and the same week age Creld2 in each sex group +/+ Mice and Creld2 -/- The difference between the weights of the mice has no significant meaning, and the suggestion is that the Creld2 deletion has no obvious influence on the weight and the growth and development conditions of the mice.
Retrospective analysis of Creld2 from death records -/- Mouse and littermate wild type Creld2 +/+ Long-term survival of mice, inclusion of 13 Creld2 mice -/- Mouse and 16 littermate wild type Creld2 +/+ Mice, the longest observation time is 312 days, and the death condition of each group is counted to draw a survival curve. As shown in fig. 9, creld2 -/- 1 mouse dies on the 182 th day and the 241 th day respectively, 11 mice survive on the 312 th day, and the survival rate of the 312 th day is 84.6 percent; littermate wild type Creld2 +/+ The mice died 1 each on day 157 and 272, and 14 survived on day 312, with a survival rate of 87.5% on day 312. Statistically, with Creld2 +/+ Creld2 in contrast to mouse -/- Length of miceThe difference of the survival rates in the periods has no statistical significance, and the fact that the Creld2 is knocked out has no significant influence on the long-term survival of the mice is suggested.
(4) Histomorphometric detection
To investigate whether the effect of knocking out the Creld2 gene on the growth and development of mouse tissues and organs exists or not, the effect is respectively exerted on the Creld2 gene -/- Mice and Creld2 +/+ The mice were stained with hematoxylin-eosin (HE) staining for various tissues such as intestinal tract, stomach, heart, brain, pancreas, spleen, lung, liver, aorta, kidney, etc., and the basic morphological structures of tissues and organs of the two mice were observed and compared. As shown in FIG. 10, the upper and lower correspondences are Creld2 +/+ Mice and Creld2 -/- The morphological structure of various organ tissues of the mouse represents a picture. Compared with Creld2 +/+ Mouse, creld2 -/- The shapes and the distribution positions of all glands in the stomach and intestinal tract tissues of the mouse are reasonable, the length and the morphological structure of villus are not abnormal, a normal liver lobule structure can be seen in liver tissues, and the boundary between the liver lobule structure and a hepatic sinus is clear and regular; in heart tissues, the texture of cardiac muscle cells is clear and visible, and the structure is not abnormal; the position and the distribution proportion of red marrow, white marrow and lymph nodes in the spleen tissue are reasonable; the structure of the bronchi at all levels in the lung tissue and the size and shape of the alveoli are not abnormal. The results indicate that the knockout of Creld2 has no obvious influence on the morphological structure of each tissue organ of the mouse.
To sum up, a gene knockout mouse deficient in Creld2 (Creld 2) was constructed based on the LoxP-Cre system -/- ) (ii) a Through the genotype identification of a plurality of tool mice used in the breeding process and obtained offspring target mice and the knockout verification of a plurality of methods on the gene and protein levels, the mice breeding process and the obtained target mice are proved to be correct, namely Creld2 -/- The mouse was successfully constructed. Further, by examining Creld2 -/- The results show that the knockout of the Creld2 gene has no obvious influence on the embryonic development, the growth process, the tissue morphological structure and the like of the mouse, namely that the deletion of Creld2 has no obvious influence on the basic phenotype, the growth development and the like of the mouse。
Example 2 Creld2 can combat intestinal injury in mice caused by noxious stimuli
1 Experimental method
Wild type mice (Creld 2) present in Creld2 were created using previous home chambers +/+ ) And Creld2 deficient knockout mice (Creld 2) -/- ) By using 60 Preparing a mouse intestinal radioactive injury model by a method of abdominal local irradiation with Co dosage of 6 Gy.
2 results of the experiment
(1) General and bowel sign investigation
General condition and intestinal signs (physical signs, activity, mucous bloody stool, diarrhea, anal bleeding and the like) research show that compared with a control group of unirradiated mice, the irradiated mice have the phenomena of reduced activity, reduced food and water intake and partial arch back on the 1 st day after being irradiated; the hair gray is scattered 4 days after the irradiation, and the hair gray 2 -/- The ratio of the occurrence of the unformed excrement in the breeding cage of the mouse is larger than that of Creld2 +/+ Mice were tall (fig. 11).
(2) Weight and survival monitoring
The weight and survival rate monitoring shows that the mice are weighed for 2 times before irradiation for 1 DAY and the DAY of irradiation to calculate the average value as the weight value before irradiation (DAY 0), then the mice are weighed DAY by DAY and the survival conditions of each group are recorded, the weight change curve and the survival curve are respectively drawn according to the weight change percentage and the survival DAYs of the mice, the weight is reduced for 5 DAYs after irradiation, and then the mice are recovered in a smaller range, creld2 -/- The mice lost more weight (fig. 12A); creld2 -/- Mice died 5 days after molding, all died by 9 days, while normal wild type Creld2 +/+ Mice died starting on day 7 after molding and all died by day 11, and the difference in survival between the two groups was statistically significant (fig. 12B).
(3) General morphology observation of intestinal tract
Gross morphological observation of the intestinal tract showed that Creld2 was observed on day 1 post-modelling, compared to the non-irradiated control mice -/- The mice begin to fill and swell with partial segment intestinal tissues, and the mice begin to fill and swell with Creld2 +/+ The intestinal tissues of the mice are swollen at days 2-3 and are full of Creld2 -/- Mice were light; on the 5 th day after model making, the intestinal tissues of the two groups of mice are highly full and swollen, the intestinal wall is thinned, and the intestinal cavity contains yellow mucus and Creld2 which can be seen by naked eyes -/- Some segmental intestinal tissues of the mice showed necrosis, and dark blue-black changes in flesh and eyes (fig. 13). Intestinal tissue engorgement and swelling occurs especially in the small intestine and occurs early in each group. The small intestine tissue is sensitive to radiation damage due to its constantly renewed nature, so that damage to the small intestine occurs earlier and to a greater extent. Measuring the total intestinal length (WI) and the small intestinal length (SI) of the mice, wherein on one hand, the total intestinal length and the small intestinal length of the two groups of mice after modeling are shortened to different degrees compared with the control group of mice; on the other hand, after modeling, creld2 was compared to the respective control group -/- The ratio of the total intestinal length to the shortened small intestinal length of the mouse is larger than Creld2 +/+ The differences between groups of mice, especially dominated by a shortened small intestine length, were statistically significant (FIG. 14).
(4) Visualization of intestinal tissue morphology
The morphology of the intestinal tissues shows that HE staining is carried out, and the intestinal tissues of the non-illuminated mice used as a control have clear and complete structures, regularly arranged intestinal villi, uniform length, reasonable number and position distribution of crypts, uniform depth and clear and visible structures; however, in the model building group, the damage degree becomes worse gradually along with the time after the model building is irradiated, and on the 1 st day after the model building, the two groups of mice have intestinal villus defect, loose structure and irregular shape; the intestinal villi injury worsened at day 3.5 after the model was made, and the part of the villi became abscission and the length was shortened (FIG. 15). Compared with Creld2 +/+ Mouse, creld2 -/- The morphological structure of the crypts of the mice is seriously damaged, the number of the crypts is reduced, the depth of the crypts is shallow, the crypts are arranged in a disorder manner, part of crypts are in an acute regeneration condition, and meanwhile, inflammatory cell infiltration can be seen; on the 5 th day after the model building, the intestinal villi are lost due to the shedding, the length is further shortened, and Creld2 -/- The villus loss of the mice is more serious, the whole shape is narrow and short, and the cryptThe cavity collapse becomes shallow and aggravates, and the number of the crypts capable of maintaining the basic morphological structure is more than that of Creld2 +/+ Mice were significantly reduced with massive infiltration of inflammatory cells in the connective tissue of the lamina propria (figure 15). The above results suggest that, compared to Creld2 +/+ Mouse, creld2 -/- The intestinal villi and crypt damage in mice is more severe.
(5) Determination of apoptosis in intestinal tissue
Cell apoptosis TUNEL staining is used for detecting intestinal tissues obtained on the 1 st day after modeling, and the result shows that the TUNEL staining positive rate of the intestinal tissues of two groups of mice subjected to radiation modeling is obviously increased compared with a control group, and the TUNEL staining positive is mainly concentrated in intestinal crypts and intestinal villus epithelium; to the extent of apoptosis, creld2 -/- The TUNEL staining positive rate of the intestinal tissue of the mouse is obviously higher than that of Creld2 +/+ Group of mice (fig. 16).
(6) Intestinal tissue cell proliferation assay
The proliferation detection of intestinal tissue stem cells shows that Ki67 (green) is selected to mark the proliferation cells 3.5 days after irradiation, and the proliferation condition of the cells is evaluated by immunofluorescence staining, so that the following results are shown: creld2 compared to non-irradiated control mice -/- Mice and Creld2 +/+ Cell proliferation in intestinal tissues of mice is obviously inhibited after irradiation molding, and proliferating cells are obviously reduced; after irradiation, compared with Creld2 +/+ Mouse, creld2 -/- The cell proliferation of intestinal tissue was low after the radioactive injury of the intestinal tract of mice occurred (fig. 17).
(7) Intestinal crypt cell proliferation assay
Targeting crypts, a key site for intestinal tissue regeneration, displaying crypt structures through immunohistochemical staining, and marking proliferating cells by combining Ki67 to evaluate the regeneration condition of the crypts. The results show that the intestinal crypt structure of the mice in the non-irradiated control group is clear and complete, and Ki67 + The cells were evenly distributed and in reasonable positions, and the proliferation of cells in crypts was good (fig. 18). After radiation modelling, creld2 +/+ The intestinal crypt structure of the mouse is loose and deformed, the cell defect appears in the crypt, the acute hyperplasia condition appears individually, and the proliferation condition is different; creld2 -/- Intestinal crypt defect of miceSevere, structural collapse, ki67 showed significant inhibition of proliferation (fig. 18).
In a word, the research of the intestinal tract radioactive injury model caused by the local abdominal irradiation of the mice shows that compared with wild mice with Creld2, the Creld2 deficiency can aggravate the signs, the gross form, the tissue form, the apoptosis, the proliferation inhibition and the repair inhibition of the intestinal injury, so that the weight is more obviously reduced, and the death of the animals is accelerated. These results suggest that endogenous Creld2 itself has a protective effect against the intestinal damage caused by noxious stimuli.
Example 3 Creld2 combats Ex vivo small intestine organoid injury caused by noxious stimuli
1 method of experiment
Small intestine organoids as LGR5 + The crypt-villus-like 3D tissue structure taking the intestinal stem cells as the core has the capability of self-renewal and differentiation, and is an ideal model for researching proliferation, differentiation and injury repair of the intestinal stem cells in vivo by simulating the physiological function and characteristics of the intestinal stem cells. From C57 mice, creld2 +/+ Mouse, creld2 -/- Separating mice to obtain small intestine crypts, in vitro culturing to obtain corresponding small intestine organoids, and adopting 1 day old small intestine organoids for carrying out 60 Co dose is radiated in 6Gy, and an ex-vivo small intestine organoid radioactive injury model is prepared.
2 results of the experiment
(1) Intestinal organoid LDH and Caspase 3 detection
LDH cytotoxicity release and Caspase 3 enzyme apoptosis activity detection were performed on day 2 after modeling to evaluate the degree of injury at the acute injury stage after modeling of each group of small intestine organoids. The small intestine organoids of each group were damaged to different degrees after molding compared to the control group. In the modeling group, the C57 group is connected with Creld2 +/+ The damage degree of the group small intestine organoids after molding has no obvious difference; compared with Creld2 +/+ Group, creld2 -/- The damage degree of the small intestine organs after model building is obviously increased, the survival rate is obviously reduced, and the LDH cytotoxicity release and Caspase 3 enzyme apoptosis activity are higher than that of Creld2 +/+ Groups (fig. 19). Growth and renewal of small intestine organoids depend on the proliferative differentiation of intestinal stem cells, and thusThe state of the intestinal stem cells after injury determines the growth state of the small intestine organoids. Therefore, the Creld2 deficiency aggravates the injury of intestinal stem cells in the radioactive injury process of the small intestine organoid, and further directly aggravates the injury of the small intestine organoid.
(2) Examination of growth of intestinal organoids
And (4) comparing the growth conditions of the small intestine organoids in the damage repair period on the 5 th day after the model building, and evaluating the damage repair conditions by indexes such as the surface area of the small intestine organoids, the budding condition and the like. The results show that after modeling, the sprouting number and the average surface area of each group of small intestine organoids are obviously reduced and are obviously lower than those of the respective control groups, which indicates that the growth states of the small intestine organoids are influenced by different degrees. In the radiation generating module, compared with the C57 group and Creld2 +/+ Group, creld2 -/- After modeling, growth of the small intestine organoids in the damage repair phase was significantly inhibited (fig. 20). Budding is a characteristic sign of intestinal stem cell proliferation in small intestine organs, and can be similar to the proliferation and division process of in vivo crypt stem cells. The results show that the Creld2 deficiency can aggravate the inhibition on the small intestine organoid damage repair, and suggest that Creld2 plays a role in the proliferation regulation of intestinal stem cells damaged by the radioactive intestine so as to influence the damage repair process.
In conclusion, the research on the radioactive damage model of the isolated small intestine organoid shows that the small intestine organoid lacking Creld2 can increase the damage degree, inhibit the damage repair process and the like compared with the small intestine organoid existing in Creld 2. These results confirm the results of the previous studies that endogenous Creld2 has a protective effect against the intestinal damage caused by noxious stimuli.
The above description is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, several modifications and additions can be made without departing from the method of the present invention, and these modifications and additions should also be regarded as the protection scope of the present invention.
Sequence listing
<110> China people liberation army navy military medical university
Application of <120> Creld2 protein or gene in prevention and treatment of intestinal injury
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Claims (9)
- The application of the Creld2 protein or gene and the synergist thereof is characterized in that the Creld2 protein or gene is used for preparing medicines for preventing and treating intestinal injury.
- Use of the Creld2 protein or gene and its potentiator for the preparation of a food for the prevention of intestinal injury.
- 3. The use according to any one of claims 1-2, wherein the intestinal injury is intestinal injury caused by stimulation such as radiation.
- 4. The use according to any one of claims 1-2, wherein the potentiating agent is selected from the group consisting of agonists, upregulators and stabilizers.
- Use of a Creld2 protein or gene and a potentiator thereof in the preparation of a medicament, wherein said medicament is for:1) Improving weight loss caused by intestinal radiation injury; or2) Delay death caused by radiation injury of the intestinal tract; or3) Improving the shortening of the small intestine length and the whole intestinal tract length caused by the radioactive damage of the intestinal tract; or4) Improving intestinal villus and crypt injury caused by intestinal radioactive injury; or5) Reducing intestinal tissue cell apoptosis caused by intestinal radiation injury; or6) Promoting the proliferation of intestinal tissue stem cells after the intestinal radiation injury; or7) Improve the defect of crypt cells caused by intestinal radiation injury.
- Use of the Creld2 protein or gene and its potentiator for:1) Preparing an agent for improving the radioactive damage degree of the small intestine organoids; or2) Preparing a reagent for promoting the repair of the radiation damage of the small intestine organoid.
- 7. A method of screening for a substance that treats or ameliorates radiation damage to the intestinal tract of an individual, comprising the steps of:a) Contacting the candidate substance with a system comprising a Creld2 protein or gene,b) And observing the influence of the candidate substance on the Creld2 protein or gene expression and activity, wherein if the candidate substance can promote the Creld2 gene expression or improve the Creld2 protein activity, the candidate substance is a potential substance for treating or improving the intestinal radioactive injury of the individual.
- Use of the Creld2 protein or gene and its potentiator for the preparation of an agent for treating or ameliorating radiation damage to the intestinal tract.
- 9. The use according to claim 8, wherein the potentiating agent is selected from the group consisting of agonists, upregulators and stabilizers.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104928254A (en) * | 2015-05-29 | 2015-09-23 | 苏州大学 | Mesenchymal stem cell for repairing radioactive intestinal epithelial injury by directionally transporting Rspol |
| CN106420687A (en) * | 2016-10-11 | 2017-02-22 | 孙君重 | Method for preventing intestinal radiation damage and application of TPA |
| CN107669692A (en) * | 2017-09-07 | 2018-02-09 | 中国人民解放军第二军医大学 | Applications of the MPLA in preparing ionising radiation and causing intestinal tract injury protective agents |
| CN110075269A (en) * | 2019-04-19 | 2019-08-02 | 中国人民解放军第二军医大学 | Murabutide causes to apply in marrow, small intestine and splenic injury protective agents in preparation ionising radiation |
| CN110170052A (en) * | 2019-06-21 | 2019-08-27 | 复旦大学 | Application of the CBP-P300 inhibitor in intestinal tract injury disease |
| CN110251669A (en) * | 2019-06-18 | 2019-09-20 | 中山大学附属第六医院 | The application of CXCL16 albumen and its monoclonal antibody in the drug of preparation prevention and/or treatment intestinal tract injury disease |
| CN114452283A (en) * | 2022-02-10 | 2022-05-10 | 中国人民解放军火箭军特色医学中心 | Use of BMNP in protecting intestinal tract from ionizing radiation damage |
-
2022
- 2022-05-31 CN CN202210612380.9A patent/CN115154587A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104928254A (en) * | 2015-05-29 | 2015-09-23 | 苏州大学 | Mesenchymal stem cell for repairing radioactive intestinal epithelial injury by directionally transporting Rspol |
| CN106420687A (en) * | 2016-10-11 | 2017-02-22 | 孙君重 | Method for preventing intestinal radiation damage and application of TPA |
| CN107669692A (en) * | 2017-09-07 | 2018-02-09 | 中国人民解放军第二军医大学 | Applications of the MPLA in preparing ionising radiation and causing intestinal tract injury protective agents |
| CN110075269A (en) * | 2019-04-19 | 2019-08-02 | 中国人民解放军第二军医大学 | Murabutide causes to apply in marrow, small intestine and splenic injury protective agents in preparation ionising radiation |
| CN110251669A (en) * | 2019-06-18 | 2019-09-20 | 中山大学附属第六医院 | The application of CXCL16 albumen and its monoclonal antibody in the drug of preparation prevention and/or treatment intestinal tract injury disease |
| CN110170052A (en) * | 2019-06-21 | 2019-08-27 | 复旦大学 | Application of the CBP-P300 inhibitor in intestinal tract injury disease |
| CN114452283A (en) * | 2022-02-10 | 2022-05-10 | 中国人民解放军火箭军特色医学中心 | Use of BMNP in protecting intestinal tract from ionizing radiation damage |
Non-Patent Citations (2)
| Title |
|---|
| 常建辉等: "P38抑制剂SB203580对小鼠辐射致死效应和小肠损伤的保护作用", 《药学学报》, vol. 46, no. 4, 12 April 2011 (2011-04-12), pages 395 - 399 * |
| 李佳等: "角质细胞生长因子对小鼠放射性肠损伤的治疗作用", 《中华临床医师杂志（电子版）》, vol. 7, no. 13, 1 July 2013 (2013-07-01), pages 3953 - 3955 * |
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