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Management of the breeding and rearing facility for microbiologically and genetically regulated cynomolgus macaques. Establishment of breeding technology for efficient breeding and research of assisted reproductive technology. Research of animal models for human diseases.
Research of animal models for human diseases.
Animal models are required for study of the human diseases. However, the relevance of small animal models such as mice to natural human in vivo physiologic and metabolic kinetics remains unclear. Large animal species may provide far more appropriate preclinical models that will more closely reflect human physiological characteristics and behavior. Among large animals, nonhuman primates may provide the best models because of their close phylogenetic relationship to humans. It is essential to develop animal models for human diseases to reveal its mechanisms and to develop new therapeutic interventions. Pathologic models in monkey includes the following; 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.

Establishment of these animal models is an essential prerequisite of the research on human diseases, and development new techniques in medical science, either. Also, these disease animal models should be used effectively as common research resources for medical science. We refer to main spontaneous and pathologic models in nonhuman primate.

Establishment of spontaneous animal models by using nonhuman primates for human diseases.  
   
  Although nonhuman primates are considered as useful animal models for human diseases, it remains that the problem of indivisual difference among monkeys.
In our primate center, by continuous investigation over 25 years, we have found several spontaneous disorders in monkey colonies. Moreover, we also found that those several age-related or congenital disorders were quite similar to human diseases.
Then those spontaneous animal models can enable us to investigate the mechanism of age-related or congenital diseases, and it also contribute to establishment of therapy.


Post-menopausal osteoporosis
Sexually mature cynomolgus monkeys show menstrual cycles and menopause similar to those in humans. Bone mass and density are therefore measured to determine post-menopausal osteoporosis and consequently to establish prevention or treatment methods for osteoporosis in humans.


Diabetes mellitus
Some monkeys in our breeding colony showed type II diabetes. Progression of the symptoms of this disease was similar to that in humans. As shown in the figure, a diabetic gradually became obese over several years. Then, suddenly they lost weight rapidly, and at the same time their blood glucose levels significantly increased.


Cardiovascular diseases
We extracted cardiac diseases that ventricular septal defects, double chambered right ventricle, valvular diseases, endocarditis and cardiomyopathy in cynomolgus breeding colony. This is the first case of muscular ventricular septal defect in a cynomolgus monkey. Turbulent blood inflow into the right ventricle through the muscular part of the ventricular septum (arrow) was observed in the short-axis view by echocardiography. [Contemp Top Lab Anim Sci. 2005;44:26-28.]


Alzheimer’s disease
In aged cynomolgus monkey brains, we can find spontaneous senile plaque formation: one of the major histopathological features in Alzheimer’s disease. Thus cynomolgus monkey is considered as an useful animal model for Alzheimer’s disease and other againg-causative neurodegenerative disorders.


Macular degeneration
We found familial macular degeneration in cynomolgus monkeys, and maintain that strain in our primate center. Macula lutea is degenerated and becomes unclear in affected eye (upper) compared to normal eye (below).


Endometriosis
Endometriosis is often found in the cynomolgus breeding colony. Endometriosis is the most severe diseases in obstetrics because of typically present a chronic pain and infertility. This figure shows endometriomas that have classic characteristics on ultrasound.


Hyperlipemia
Some monkeys showed hyperlipemia even in our strict nutritionally controlled colony. Such monkeys tended to belong to a certain family line. An obese monkey and lacteal serum collected from this monkey are shown in this figure.

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Development of animal model by using nonhuman primates
Even today, although biomedical techniques have been well improved, it is still unknown that the onsets and the pathology of emerging infectious diseases or aging-causative disorders, and it is an urgent mission to establish preventive and therapeutic tools such as vaccines, drugs, and techniques for those diseases. Since there are many pathogens that are infected with only primates, it is necessary to use primate animal models for investigating pathologies or evaluating drug developments. In our primate center, we are working on the research aiming for the establishment of primate animal models and applied investigations by using them.


Hepatitis C virus
Hepatitis C virus (HCV) is known to infect to human and chimpanzee but not generally available non-human primates. However, chimpanzees are endangered and are hardly available, and if possible, the use is extraordinarily expensive. To break through the difficulty, we have started on the development of a surrogate model of HCV infection using tamarins and marmosets infected with GBV-B. Fig: Marmoset.


Hemodyscrasia (Hematopoietic disorders)
Cytokine-mobilized peripheral blood stem cells are widely used for autologous and allogeneic transplantation therapies to treat hematological malignancies such as leukemia and lymphoma. We established safe and efficient method for collecting cytokine-mobilized peripheral blood cells (leukapheresis) in monkeys.


AIDS
The non-human primate model on AIDS has provided a lot of breakthroughs required for the development of new therapeutic medicines. Presently, extensive study for the establishment of effective anti-HIV vaccines have been ongoing. Fig: EM picture of human immunodeficiency virus type I (HIV-1) particles.


Prion disease
We have established the animal model for human prion disease by using squirrel monkeys. In affected monkey brains, we can find spongiosis in hippocampus area (Fig. A), and infectious prion protein is immunostained (Fig. B).


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.

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