Induced disease models

Induced disease models

Animal are used on a large scale in medical research. They are basically used to study the biological mechanisms that maybe involved or to identify the genetic basis of both normal and pathological cellular mechanisms. These animals are also widely used as models to explore the possible treatments for human diseases.

Genetic diseases have been very vastly and successfully studied using these animal based models. Many of these animal models have been discovered by random chance and some were discovered by screening of inbred animals. Mouse models have been successfully used to study diseases which have been possible only because of stem cell lines and also with the development of specific methods for the introduction of mutations into these cell lines. In case of other animals development of embryonic stem cell lines to be used in animal models has been very difficult. These animal based models can be classified as the following:-

INDUCED (EXPERIMENTAL) DISEASE MODELS

These are those models which are based on healthy animals. The conditions which are to be studied in the animals are introduced into them through a set of experiments. Since the conditions are experimentally introduced it allows for a choice of selection of the species. Some of these induced models fully resemble the etiology, course and pathology of the target disease in humans.

SPONTANEOUS ANIMAL DISEASE MODELS

These are those models which use the naturally occurring genetic mutants. These kinds of models display the isomorphic phenotypic similarity between the disease in the animals and the human alike. This results in similar treatments for the human patient as compared to the model organism. Therefore these models are used in discovery of new methods for treatments of the human diseases.

GENE-MODIFIED DISEASE MODELS

These are those models which are developed by the use of genetic engineering and embryo manipulation techniques. A huge amount of models have been developed based on these models and the numbers of models based on these are still increasing rapidly.

NEGATIVE ANIMAL MODELS

These are those category of models in which a certain disease does not develop even after a treatment which results in disease in other animals. There always occur only a certain amount of vulnerable species and the rest of the insensitive species are regarded as the negative models for that specific human pathogen.

ORPHAN ANIMAL MODELS

These are those models which are used for the description of a functional disorder. These are those disorders which have a natural occurrence in non human species but they are still not yet characterized in humans. These are acknowledged only when a similar human disease is identified.

“Selection criteria for animal models should:

  • Accurately mimic the desired function or disease
  • Species Availability
  • Data extrapolatable to man
  • Be available to multiple investigators
  • Be handled easily by most investigators
  • Survive long enough to be functional
  • Fit available animal housing facilities
  • Be of sufficient size to provide multiple samples
  • Be polytococous (multiparous) so that multiple offspring are produced for each gestation”.

(http://netvet.wustl.edu/species/pigs/pigmodel.txt)

Animal models are essentially used to study the different diseases. In cases of animal models where the model animal is small as in the case of mice its comparison with the natural in vivo physiological and metabolic process in the human beings remains quite blurred. Hence the use of large animals as model organisms provides much better preclinical models which demonstrate the human physiological characteristics and behavior in a much better way when compared with the small animals. In these large animals, non human primates present scientists with the best models as they are phlogenitically very close to the human beings. These models help in revelation of mechanisms of the human diseases and also result in development of new therapeutic mechanisms for their treatment.

“Pathological models in case of monkeys included;

  1. Spontaneous disease model that extracted from the breeding colony.
  2. Development of experimental animal models for chronic diseases.
  3. Infectious diseases models in the highly controlled biosafety laboratory facility”. (http://tprc.nibio.go.jp/eng/research/disease_e.html)

(http://tprc.nibio.go.jp/eng/research/disease_e.html)

Establishment of spontaneous animal models by using nonhuman primates for human diseases.

Non human primates are generally considered to be useful models for human diseases still several spontaneous disorders have been found in case of monkey colonies. Also it was found that several age related or congenital disorders were very similar to the human diseases. Therefore these models can help us to study the process of age related diseases and also may result in the development of a therapy.

Post-menopausal osteoporosis

The sexually mature cynomolgus monkeys exhibit the menstrual cycles and menopause which very much resemble the same process in human beings. Therefore the mass of the bone and its density are measured in case of these monkeys which help in the study of post menopausal osteoporosis by acting as the model organism.

Diabetes mellitus

A few monkeys in the colonies those were breeded exhibited type II diabetes. These when closely observed showed development same as in the case of humans. As can be observed from the graph, a diabetic slowly gained weight through the years and became obese. Then all of a sudden they lost weight and also their blood glucose levels increased.

Alzheimer's disease

“In case of the aged cynomolgus monkey brains, spontaneous senile plaque formation could be found which is one of the major histopathological features in Alzheimer's disease. Thus these monkeys are considered as an useful animal model for Alzheimer's disease and other ageing-causative neurodegenerative disorders”. (http://tprc.nibio.go.jp/eng/research/disease_e.html)

Development of Animal model by using non human primates

Onsets and the pathology of some emerging infectious diseases or ageing causative disorder are still unknown and it's very important to develop tools such as vaccines and drugs against such conditions. Since there are many pathogens which get infected only by the primates it is necessary to use primate animal models for evaluating drug developments.

(http://tprc.nibio.go.jp/eng/research/disease_e.html)

Hepatitis C virus

“Hepatitis C virus (HCV) has been known to infect human and chimpanzee. But, chimpanzees are an endangered species and so are very rarely available for ffor experimental set ups. Due to this problem the development of a surrogate model of HCV infection using tamarins and marmosets infected with GBV-B has been taken up”.( AIDS
With the use of non-human primates for the study of Aids many new breakthroughs which were essential for development of new vaccinations and drugs have been studied upon. At present a lot of studies are undertaken to establish anti-HIV vaccines.

Parkinson's disease

“A model of Parkinson's disease in cynomolgus monkeys was established by the chronic treatment of MPTP (1-metil-4-phenil-1,2,3,6-tetrahydropyridine). MPTP monkeys show rigidity of limbs, bradykinesia, facial expressionless (see figure), and severe tremors in their limbs. When tremors in the forelimbs become severe, MPTP monkeys have trouble gripping their food and thus sometimes drop it”. (http://tprc.nibio.go.jp/eng/research/disease_e.html)

Animals which are used to study human diseases are selected based on their similarity with regards to the genetics, anatomy and physiology. These are also widely used because they provide an unlimited supply and an ease of manipulation. Rodents are one of the most commonly used for such studies. A vast amount of studies have been done using rats, mice, gerbils, guinea pigs and hamsters. Also in these animals mice is mostly used as their genome is very much similar to that of human's, also they are very easily available, easiness with which they can be handled, high reproductive rates and low cost of usage. Other most commonly used experimental organisms included fruit flies, zebra fish and baker's yeast.

Methods of Inducing Human Disease in Other Organisms

Most model organisms have similar genomic makeup as the humans but they do not uptake diseases as a human does, therefore there is a need by scientists to alternate there genomes so that human disease states can be taken up by these models. In an attempt to alter the genes of a mouse model for human disorder the scientists need to know what exactly the cause of the disease is so that they can introduce that mutation into the mouse geneome.

Scientists have approached these tasks in two main ways: one that is directed anddiseasedriven, and the other that is non-directed andmutationdriven (Hardouin & Nagy, 2000). Radiation and chemicals are used for mutations in case of non-direct mutation driven methods. Common directed techniques include transgenesis, single-gene knock-outs and knock-ins, conditionalgenemodifications, andchromosomal rearrangements.

Large-Scale Mutation Screens

These as the name implies attempt to mutate the animal model genomes. Then are screened to determine which one's show phenotypes that are similar to human diseases. Therefore rather by using diseases mutations these type of methods are based on screening the different phenotypes. The best way to cause mutation in organisms is by either exposing them to x-rays or by chemical treatment using N-ethyl-N-nitrosourea (ENU). X-rays result in removal of large chunks of DNA or translocation mutation involving multiple genes (Bedellet al., 1997a), while as ENU results in single gene mutations or point mutations (Hardouin & Nagy, 2000). This can result in different effects whereby certain function maybe reduced or gained as a result of mutation(Rosenthal & Brown, 2007), and these are frequently used to screen model organisms like the zebra fish.

Transgenesis

Transgenesis is a much more directed approach when compared with X-rays and the ENU. Foreign genetic information is added into the nucleus of embryonic cells which results in the limitation of the expression of the genes. This can be done using two methods whereby the foreign DNA can be directly injected into embryo or also retroviral vectors can be used and transgene inserted into the host organisms DNA. Mouse gene were transferred for the first time in the year 1980 (Hardouin & Nagy, 2000); but the methods used for this purpose were not good enough. The foreign DNA was integrated into only a very few embryos and were passed on in a very inconsistent was from one generation to the next. Since transgenes are inserted into variable random sites in the genome they were not actually expressed every time and it depended more on the location of these genes. Scientists have also been developing ways to increase the size of DNA freagments which can be used in transgenesis for cloning in the yeast artificial chromosome or the bacterial artificial chromosome. These larger transgenes are more likely to contain regulatory sequences necessary for normalgeneexpression and are usually more comparable to the endogenousgene(Bedellet al., 1997a). Due to all these the use of transgenic mice has increased many folds in the past few years.

Single-Gene Knock-Outs and Knock-Ins

Gene Knock outs and knock in models are the different ways to target a mutation at a specific point on the gene. These methods are highly effective in cases where a single gene is the main cause of a specific disease. Knock-out mice are those which carry an inactivated gene which results in less expression of the gene and hence also loss of function. Whereas Knock in mice are created by inserting a transgene at locations where they are over expressed. During the past few years almost 3000 genes have been knocked out of mice and out of these mostly genes were related with diseases (Hardouin & Nagy, 2000).

In both these techniques animals are created by inserting a specific mutation into the endogenous gene. These genes are then passed onto the next generation as a result of breeding. Embryonic stemm cells play an important role in this technology. Embryonic stem cells can result in all cell lineages when they are injected into the blastocysts, these can then be altered genetically and then selected for the required changes.

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