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Mad Cow Disease and Transgenic Animal Research
With the rapid development of molecular biology and molecular genetics, people's control and prevention of animal diseases has become more and more inclined to transgene technology. In recent years, the outbreak and spread of mad cow disease in Europe and the United States, it is a kind of conformational disease of the host autologous prion protein, and it can not carry out immune recognition. However, the research on the pathogenesis of the disease remains to be in-depth. At present, people's prevention of the disease. It is limited to prevention and cannot be treated. Therefore, the cultivation of transgenic animals will bring good news for the prevention and control of these diseases. In the prevention and treatment of animal infectious diseases, we use a variety of methods, including immunization, health management and scientific treatment, although many scientific methods play a role in the control of diseases, such as animal experiments, molecular biology research and basic pathology studies. And so on, but many infectious diseases still plague us, but the best way to control infectious diseases is to breed good disease-resistant animals to stop the disease. This involves the study of transgenic animals and requires people to conduct in-depth studies. Mad cow disease has been a fierce infectious disease that has plagued humans. It is caused by Prion Protein (PrP), which is characterized by long latency, mental disorders, ataxia, hindlimbs, and frantious neurological symptoms. disease. Recent studies have found that the structure of prion protein changes from the alpha helix to the beta sheet and causes mad cow disease, and that human Creutzfeldt-Jakob disease and scrapie disease are all related to prion protein and are animal-borne spongiform encephalopathy ( One of the TSEs), BSE was first discovered in the United Kingdom in 1986 and subsequently spread to many European countries and regions, causing huge losses to the cattle industry in the United Kingdom and Europe. In recent years, due to the prevalence of BSE, the emergence of variant human Creutzfeldt-Jakob disease (vCJD) caused by the same virulence factor PrP has caused panic in the world for mad cow disease, which has caused a lot of economic losses and harmed human health. More and more people are paying attention to it. From the point of view of the occurrence and development of mad cow disease, humans need to increase scientific research and make prevention work. It is precisely because mad cow disease is not yet curable. Therefore, the most effective measures should be to make species selection and breeding work if transgenic breeding is carried out. Cows with anti-PrPSC configuration-transforming genes will to a great extent prevent the occurrence of mad cow disease. At present, there have been breedings of such transgenic cattle in Japan and they have been successful, thereby increasing the animal's resistance to disease. Human control of disease brings good news. 1 Transgenic Research on Mad Cow Disease Many scientists used genetically engineered mice to analyze PrP gene structure during the etiology of mad cow disease, and developed transgenic anti-PrP monoclonal antibodies using transgenic mice. Clinical trials have yielded effective results. Makes humans have a scientific evaluation and diagnosis basis for mad cow disease at the molecular level. However, there is currently no effective vaccine or drug that can eradicate mad cow disease. The prevention and control of this disease still focuses on prevention. Since there is a clear orientation for the cause of mad cow disease, we only need to extract other animal anti-PrP genes for cattle transgenic selection. Breeding the genetically modified cattle will better prevent the occurrence of mad cow disease, which requires a lot of genetic research. Japan has already taken the lead in this regard and should promote it globally. 2 Research Progress of Transgenic Animals Transgenic animal research is a method in which humans have the purpose, plan, evidence, and foresight to change the genetic composition of animals according to their own wishes. It is based on modern molecular biology and animal embryo and gamete bioengineering technologies. Experimental Technology. There is no doubt that this is a very challenging study. 2. 1 Research History of Transgenic Animals In 1982, Nature published the message that Brinster and Palmiter used transgenic technology to obtain super mice with exogenous GH genes, which caused a worldwide sensation. This is the first time an exogenous gene has been expressed in animals. In 1985, Americans used the method of transferring GH gene, GRF gene and IGF1 gene to produce transgenic rabbits, transgenic sheep and transgenic pigs; the same year German Berm transferred human GH genes to produce transgenic rabbits and transgenic pigs; 1987, Australia Transgenic sheep produced transgenic pigs by injecting bovine GH gene. Due to pathological reactions, valuable transgenic animals have not been cultivated at this stage. In 1987, Gordon et al. of the United States reported for the first time that the human tPA gene was expressed in the mouse mammary gland tissue. In the next four years, several products with commercial development value were successively produced in animal mammary glands. In 1991, the British expressed the human antitrypsin gene in the sheep's mammary gland; in 1992, Velander in the United States reported that human C protein gene was expressed in the mammary gland of pigs. Since then, public reports have decreased due to commercial purposes, but bioreactor research has been ongoing, and some people have also studied using the bladder as a bioreactor. In addition to the above applied research of bioreactors, great progress has also been made in animal breeding. Thanks to the country's strong support, China has made great progress in research on transgenic animals. Fast-growing transgenic pigs were obtained using the sheep's MT/porcine GH fusion gene method. Fast-growing transgenic rabbits were obtained in 1990. Fast-growing transgenic sheep were obtained in 1991. 2. 2 Production methods of transgenic animals 2.2.1 Microinjection of pronuclear embryos This method was invented by American Gordon and is one of the methods for producing transgenic animals that are widely used and stable. In this method, the foreign gene is injected into the fertilized egg, and then the genetically manipulated fertilized egg develops into a new animal individual. This method is simple, the transgene speed is fast, the size of the exogenous gene fragment is not strict, and the proportion of chimeras is small. Molecular biology analysis of transgenic animals can yield more information about gene expression and knowledge of gene regulation. Gordon inserted the replication origin and promoter of SV40 into the bacterial plasmid pBR322 with the TK gene of the herpes virus, then injected it into the pronucleus of the fertilized mice, and implanted the plasmid-injected embryo into the oviduct of the pseudopregnant mother mouse. Afterwards, the born mice were tested by Southern blot hybridization to check whether their genome contained homologous fragments of the injected gene. Of the 78 mice born, two were considered positive for the transgene. Due to conditions, Gordon did not get live transgenic mice at the time, but this great attempt confirmed that foreign genes can be integrated into the host genome by this method, opening up a new path for future research. . Following Gordon's report on the microinjection of transgenic mice, Palmerer's 1982 report caused a stir in the life sciences. Palmiter linked the rat growth hormone gene with the deletion of the 5' regulatory region to the mouse metallothionein I gene promoter, and then injected the fusion gene into the male pronuclei of the fertilized mice, yielding 21 mice, of which 7 were Transgenic positive mice. In the positive mice, the 2nd mouse had a body weight of 1.87 times that of the average weight of the non-transgenic littermates at 74 days after birth, which is known as the "giant mouse" event. Hammer et al. successfully produced transgenic rabbits, sheep, and pigs using this method. The above three studies were considered to be milestones in animal genetic research. 2. 2. 2 Retroviral vectors infect early embryonic animal embryos. This technique is characterized by the use of retroviruses to integrate a portion of the DNA of a virus into a host cell when infected by the host. Through this effect, one can construct in vitro. The gene is recombined into a viral vector, and the animal cell is infected with the virus carrying the desired gene to achieve the purpose of transferring the virus-carrying target gene into the animal cell. This technique was reported as early as 1974. When using a retroviral vector technology for transgenesis, it is usually carried out using animals' early embryonic cells. They are co-cultured with the virus, and then the virus-infected cells are transferred to appropriate maternities to complete the development process, and transgenic animals are obtained. The advantage of retroviral vector technology for animal transgenesis is that it can be used for the transformation of multicellular embryos, which is especially used in the transformation studies of chickens. Its disadvantages are less chance of obtaining homozygous transgenic animals, complex construction of viral vectors, limitation of the size of the transferred foreign genes, and possibly the introduction of viral vector sequences at the same time as the transgene, which is not required by us. . 2.2.3 Sperm vector method As early as 1971, Bracket and his collaborators began the pioneering work of sperm-mediated exogenous DNA transfer: sperm were exposed to purified SV40 DNA (H3-labeled adenine) after sperm Radioactivity detected in the head. Their results showed that heterologous DNA can enter mammalian sperm, and sperm can carry foreign DNA into the oocyte. Rottman et al. modified the sperm vector method by modifying the exogenous DNA with liposomes prior to co-incubation with the spermatozoa and the liposomes interacting with the DNA to form a liposomal DNA complex. This complex is relatively easy to fuse with the sperm cell membrane and thus enters the cell interior. The improved sperm carrier method obtained satisfactory results in the production of transgenic chickens. A 12-day-old chicken embryo was found to have a 26% transgene positive rate by Southern blot hybridization. The most ideal positive rate was 92%. Experiments also showed that the exogenous DNA was not integrated into the host genome but was present as an epibody outside the chromosome. 2.2.4 Embryonic Stem Cell Technology Embryonic stem cells (ES) are pluripotent cell lines established by in vitro differentiation inhibition culture of early embryos. They maintain their terminally differentiated state in vitro and can be passaged and proliferated. ES cells are similar in development to the cells of the inner cell mass of early embryos and, when injected into the blastocyst space, can participate in the formation of various tissue chimeras including gonads. ES cells have two distinct characteristics, differentiation potential and normal euploid karyotype similar to early embryonic cells. They are ideal models for the study of mammalian individual development, embryonic differentiation, and genetic mechanisms of traits. In the field of transgenics, ES cells are recognized as a promising experimental material for studying gene transfer and gene mapping integration. 2.2.5 Primordial Germ Cells (PGCs) mediated transgenesis technology is similar to ES cell technology in terms of principles and methods. The application of PGCs technology has obvious advantages in producing transgenic poultry. Brinster et al. Attempted the feasibility of transferring spermatogonia between individuals in the sire. The investigators implanted the PGCs of the ZFlacZ donor mice into the fine tubes of the C57BL/6 STL hybrid mouse. The results of the study showed that the transplanted spermatogonia was transplanted. The post-PGCs can develop into fertilized sperm cells and produce offspring. Naito et al. used this method to make transgenic chickens. Whether large livestock PGCs can inhibit differentiation and proliferation like mouse ES cells can not yet reach a definitive conclusion. If so, this will bring about a revolution in animal genetic transformation. Studies have confirmed that PGCs are fertilized. This technology combined with gene mapping integration technology is very likely to get a pure line of transgenic livestock in a short period of time. 2. 3 Application of transgenic animal research 2. 3. 1 Promote animal growth, increase livestock product yield, improve product quality Following Palmerer's introduction of rat GH gene into mouse genome to obtain giant mouse, cattle, sheep and human GH The genes were also introduced into the mouse genome one after another. The resulting transgenic mice grew four times faster in the fast growing phase (5 to 11 weeks of age) than the control mice. The mechanism by which exogenous GH regulates growth is thought to stimulate the synthesis and secretion of insulin-like growth factors in the host animal. The results of some studies conducted by humans on the transfer of bGH pigs showed that the daily gain of transgenic pigs increased and the feed conversion rate increased. Using genetically modified rams to mate with 43 ewes, 85 lambs were born, of which 43 (50.6 %) were GM-positive. When lambs sheared at 14 months of age, the average net hair yield of transgenic sheep was 62% higher than that of half-sib non-GM sheep, and the increase in gross wool production of male lambs (92%) was higher than that of female lambs (34%). There was no significant difference in wool fiber diameter, medulla, and age-old weight. In addition, Powell et al. introduced the hair keratin type II intermediate filament gene into the sheep genome. The transgenic wool was bright and shiny, and the wool lanolin content was significantly improved. 2. 3. 2 Utilization of transgenic animals as bioreactors On April 1, 2002, the University of Georgia and AviGenics of the United States announced in the April issue of the British journal Natural Biotechnology that they had been awarded to the field of transgenic research in poultry. Breakthrough progress has led to the development of cloned chickens that can produce genetically modified eggs containing the protein needed by the body. It will join the ranks of GM animals that can produce medicinal proteins such as sheep, goats and rabbits, and it is expected to become a new type of living biological reaction synthesizer and animal pharmaceutical factory. The use of transgenic animals for the production of target gene products is another important area of ​​application for transgenic animals. The foreign gene is transferred into the animal to obtain a transgenic animal, and the target product is obtained from the animal's milk or blood, instead of the conventional fermenter. Through gene engineering technology, the gene expression level of transgenic animals can be continuously improved, so that the yield of gene products can be continuously improved. The use of transgenic animal production instead of fermentation tanks will greatly reduce the cost and obtain considerable economic and social benefits. 2. 3. 3 Animal breed improvement It is clear that the transfer of beneficial genes into recipient animals will provide a very effective new breeding method for the improvement of livestock breeds. It can be restricted to the use of beneficial genes between traditional breeding methods and livestock breeds that can be crossed. Scientists have obtained transgenic materials such as genetically modified fish, chickens and pigs through genetically modified materials. Chinese scholar Zhu Zuoyan used microinjection technology to obtain genetically modified goldfish that grew twice as fast as the control group, as well as the hormone-transformed salmon, red snapper, silver carp, mirror carp, and mud carp. Currently, transgenic chickens are obtained using transformation techniques using retroviruses as vectors. Influenza virus can infect most birds and mammals, and mice can selectively resist influenza virus infection. Studies have shown that this resistance is related to the expression of its Mx gene. Garber et al. inserted the sense and antisense strands of the cloned mouse Mx gene into the replication-competent avian retrovirus vector and transfect it into chicken embryonic fibroblasts (CEFs). The results showed that only the CEF transfected with the retroviral vector inserted into the sense strand can produce Mx protein, and at the same time, it shows that the CEF transfected with the sense retroviral vector of the sense strand can infect human influenza virus and bird flu virus. Resistant, but not resistant to coated RNA virus, herpes stomatitis virus (VSV). The successful breeding of the transgenic cattle with anti-PrPSC gene has brought a new approach to the prevention and control of mad cow disease. 2. 3. 4 Establishment of Animal Models for Diagnosis and Treatment of Human Diseases Scientists transferred oncogenes to mouse fertilized eggs and obtained mice with oncogenes. These mice provide an ideal animal model for the study of the pathogenesis of cancer genes, the regulation of cancer gene expression, and the effects of new drug treatments. Similar animal models can be used to study many genetic-related diseases, such as blood diseases. Transgenic animal models are also good materials for the study of gene therapy, such as the development of treatment programs for specific diseases, drug trials, and the like. Human progress in the pathogenesis of diseases such as AIDS is extremely slow, because there is no suitable small animal model to study the infection of HIV1 to the host cells and the subsequent development process, so it is also difficult to develop effective diagnosis, treatment and preventive measures. . The application of animal transgenic technology provides great convenience for solving animal models needed for such research. Snyder et al. introduced the human CD4 fusion gene into the rabbit genome and successfully produced an animal model that can be used to study HIV-1 infected host cells. HIV1 can infect common rabbits, suggesting that hCD4 rabbits are more susceptible to HIV1. The establishment of these models will undoubtedly accelerate human understanding of AIDS and take appropriate measures to prevent and treat diseases. 2.3.5 The production of allogeneic organ transplants for animal organs that can be used for human organ transplants may be an effective way to solve the ubiquity of organ shortages worldwide. At present, pigs are the most studied animals for organ donors. Pigs as donor animals for human organ transplantation have the following advantages: Short gestation period, high number of litters, rapid growth of offspring, and no ethical issues. What's more important is that the organs of pigs at different developmental stages, such as the heart and kidneys, are similar in size to the organs of people of different ages and are very likely to replace some of the patient's organs. 3 Looking forward to more than a decade after the advent of GM animal research, through the unremitting efforts of scientists from all over the world who have devoted themselves to this field, their brilliant prospects have begun to emerge. The application of BSE to the prevention and control of BSE is still in its infancy. There is still a considerable distance between the current research level of this technology and its enormous social and economic benefits. Therefore, it is really necessary to link the prevention and treatment of diseases with scientific research. With the help of genetically modified animal research, humankind will be free from the problems of mad cow disease and other zoonosis as soon as possible, I believe the prospect of this study is brilliant.