疾病动物模型,基因修饰胰腺癌动物模型 z-bio 2021-03-10 617

　　[Model mechanism] In the early diagnosis and treatment of pancreatic cancer, it was found that the precancerous state of pancreatic cancer, that is, the molecular genetic abnormality of pancreatic duct epithelial tumors, is directly related to pancreatic cancer. Pancreatic duct epithelioma is considered to be a precancerous state of pancreatic cancer, which originates from the columnar epithelium of the pancreatic duct. Recent studies have shown that pancreatic ductal intraepithelial tumors originate from vesicular heart cells. Under the action of various tumor-causing factors, vesicle heart cells transform into renal tubular heart cells-tubular cells, forming a tubular complex, and gradually evolve into pancreatic duct intraepithelial neoplasia (pancreatic duct intraepithelial neoplasia) ). , PanIN). Blister heart cells are closely related to the heterogeneity of pancreatic duct intraepithelial tumors. In addition, research indicates whether vesicle heart cells can be achieved. The transformation of renal tubular cells is related to the mutation subtype of K-ras gene. In other words, K-rasG12D can cause this transformation, but K-rasG12D mutant mice cannot.

　　[How to build a model]

　　1. K-Ras knockout mouse model uses LoxP/Cre-specific recombination technology to activate K-rasG12D through the pancreas-specific promoter Pdx-1. All mice specifically produce PanIN at each stage. This is the PanIN model of the K-ras C12D mouse. Except for the K-ras gene mutation detected in this model, there are no mutations or deletions in P16, P53, and Smad4. The cell proliferation rate of PanIN cultured in vitro is similar to that of primary pancreatic cancer. Observed by optical microscope, colonies can be formed on soft agar. With the extension of culture time, the colonies increase, and PanIN cells grow to a certain extent. It has the biological characteristics of malignant transformed tumor cells.

　　2. After mating the P53 gene mutant K-rasC12D mice targeting the K-Ras gene mutation and the mouse pancreatic cancer model with the inactivated mutant P53R172H mice, all the mice were transiently invasive pancreatic ductal carcinoma (pancreatic cancer). Ductal adenoma, pancreatic ductal adenoma, PDA) and visible liver, lung and intraperitoneal metastasis can specifically develop a variety of cancers. This is the K-rasG12D/P53R172H mouse PDA model.

　　3. The P16 gene mutation and mouse pancreatic cancer model targeting K-Ras gene mutations K-rasG12D mice (all mice that specialize in PDA production) that bred to all P16-deficient mice died within twelve weeks, twelve The duodenum usually spreads to organs such as mice and kidneys. This is a PDA model of K-ras G12D/P16 deficient mice.

　　4. K-Ras gene mutation and DPC4 gene targeted mutation mouse pancreatic cancer model makes K-ras G12D mice mate with Smad4-deficient mice. These two synergistic effects do not directly lead to the development of aggressive pancreatic cancer, but The development of mucosal cysts. Pancreatic cancer develops only when the P53/P16 gene that causes sexual lesions and lesions is mutated. [Model Features] PanIN's histomorphological classification is currently mainly obtained through time-controlled transgene or gene targeting technology. It is impossible to obtain such a morphological basis in clinical practice, which is difficult. The animal model of transgenic pancreatic cancer is basically similar to human pancreatic cancer. The pattern of metastasis is most similar to that of human tumors. Because you can study the early stages of tumor occurrence, you can diagnose the cause of pancreatic cancer and intervene early. after research. The effect of sexual treatment.

　　[Model Evaluation and Application] PanlN-1A, PanIN-1B, PanIN-2, PanIN-3 can be classified according to the degree of PanIN pathology. The specific classification criteria are as follows. Mucosal cell hyperplasia, non-nipple formation and atypical lesions are PanIN-1A, nipple duct epithelial hyperplasia and/or adenomatous hyperplasia, and mild atypical hyperplasia lesions are PanIN-1A. -1B; nuclear polarity disappears and multinucleation occurs. Grade 2 ductal epithelioma-like hyperplasia is moderately atypia, PanIN-2, which usually eliminates cell polarity and appears nuclear atypia. However, the basement membrane is still intact, and ductal epithelioma-like hyperplasia is grade 3.