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2011年  第32卷  第1期

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综 述
The development of efficient ways to predict, prevent, diagnose and treat human diseases is of great interest to human society and is a focus of life science research. It is widely believed that all human diseases may be attributed to the interaction between genetic and environmental risk factors, and this interaction influences the genesis, course, drug response and outcome of the diseases. The most effective approach for research into human diseases is the clinical study, but this can be hampered by disease heterogeneity, marked individual differences and the difficulty in tracking the history and course of a disease. Additionally, no study should be performed on humans without preclinical assessments in non-human animals. The best strategy for research into human diseases is to use animal models that mimic the genesis, course, drug response and outcomes of human disease and where the etiology, genetic background and environmental factors can be strictly controlled, unfeasible in clinical studies of humans. However, there are many problems associated with the study of animal models for human disease, some of which are based on misunderstanding. For this special issue of Zoological Research we discuss these problems and misunderstandings.
Cancer is the second leading disease causing human death. Pre-clinical in vivo studies are essential for translating in vitro laboratory research results into the clinic. Rodents, including the mouse and rat, have been widely used for pre-clinical studies due to their small size, clear genetic backgrounds, rapid propagation, and mature transgenic technologies. However, because rodents are evolutionarily distinct from humans, many pre-clinical research results using rodent models cannot be reproduced in the clinic. Non-human primates (NHPs) may be better animal models than rodents for human cancer research because NHPs and humans share greater similarity in regards to their genetic evolution, immune system, physiology and metabolism. This article reviews the latest progress of cancer research in NHPs by focusing on the carcinogenesis of different NHPs induced by chemical and biological carcinogens. Finally, future research directions for the use of NHPs in cancer research are discussed.
Sleep/circadian timing depends on several neurotransmitter systems, including 5-HT, NE, DA, Ach, GABA, etc. These neurotransmitter systems play critical roles in mental, emotional and cognitive functions in the brain. Dysfunctions of these systems not only result in sleep disorder, but are also related to many psychiatric and neurodegenerative diseases. Sleep disruption is tightly associated with an increased susceptibility to a broad range of psychiatric and neurodegenerative diseases, such as depression and Parkinson diseases. Non-human primates, especially the rhesus monkey is an excellent biomedical model for human sleep and CNS diseases. Establishing nonhuman primates’ model of mental disorders and monitoring the sleep changes during the development of the model will help us to know more about the relationships between sleep disorder and psychiatric and neurodegenerative diseases. Sleep disorder as an early marker for psychiatric and neurodegenerative diseases would permit early intervention of these diseases and draw attention to the potential therapeutic benefits of normalizing sleep rhythms in individuals with brain pathologies.
Diabetes is the third most severely chronic disease after cardiovascular disease and cancer. World Health Organization (WHO) estimated 220 million diabetes patients worldwide in 2009. The rational animal models of diabetes are necessary for understanding the mechanisms of diabetes, diagnosis and prevention of diabetes as well as screen and evaluation of new drugs for diabetes treatment. Compared to other animal models of diabetes, the causes and symptoms of diabetes of nonhuman primates is more like human diabetes. We here reviewed the reported nonhuman primate models of diabetes based on the sources they were generated; especially focused on three models, Macaca mullata, M. fascicularis, Tupaia belangeri. Furthermore, we discussed the perspective development of nonhuman primate models of diabetes mellitus.
Hepatitis C virus is a prevalent and globally distributed human pathogen that seriously harmful to public health. However, the development of therapy and vaccine was impeded by the lack of suit small animal models. Herein, we introduce the characters of HCV replication. Taken the HCV cellular receptors as the viewpoint, the potentiality of tupaia as hepatitis C animal model is discussed at the molecular level by comparing of present animal model.
Hepatitis B virus (HBV) infection is one of the important health problems worldwide, especially in China. Feasible and effective animal models of HBV infection in vivo are prerequisite for the HBV-related basic and clinical studies. Located in the highly prevalent region of HBV and hepatocellular carcinoma (HCC), the laboratoryof Guangxi Cancer Institute has focused on the cause, pathogenesis and chemoprevention of HCC, and has started the work of establishing tree shrew (Tupaia) models of HBV infection in vivo since the early 1980s. This paper provides an overview of the research process, and highlights the new progress on the chronic infection of tree shrews after inoculated with HBV neonatally in vivo.
We outline the historical research on the laboratory tree shrew in China and discuss its current research trends. Five key aspects of applied research are emphasized in this review, including quality control standards for laboratory tree shrews, the establishment of an inbred colony, commercial preparation of major molecular and cellular research tools, further research on tree shrew models for human diseases, and the establishment of the tree shrew seed institution at state level.
研究论文
To provide fundamental basis for the tree shrew models of human diseases, we examined and compared the physiological and biochemical indexes between wild and laboratory tree shrews. Blood samples were taken from 54 wild tree shrews that were housed in laboratory for 1 − 2 months, and from 54 first-generation of the laboratory tree shrews; each group had nearly equal male and female composition. Some of the first reported physiological and biochemical indexes were showed no significant differences between genders, and these indexes in laboratory tree shrews were as follows [medium (inter-quartile range) ]: CK 1449 (956) U/L, CTNI 5.94 (7.23) μg/L, TBA15.6 (19.7) μmol/L, FRUC 393.5 (80.8) μmol/L and LDL-C0.36 (0.32); and in the wild tree shrews, 986 (564) U/L, 4.01 (4.10) μg/L, 20.0 (20.6) μmol/L, 379.0 (104.0) μmol/L and 0.46 (0.23) mmol/L, respectively. In the laboratory tree shrews, the variations of physiological and biochemical indexes were smaller, but the mean values of some indicators related to liver and heart functions became higher. These data would be valuable for the development of tree shrew models of human diseases.
Tupaia (Tupaia belangeris chinensis, tree shrew) as a new experiment animal in medicine are non-rodent, small animals and close to primates in evolution. Experimental animals infected with viruses will affect the animal’s health, interference experiment, and even endanger the operator’s safety. Therefore, the viral infection in experimental animals has long been considered an important part of quality control. Lack of clearer viral natural infection information on the T. belangeris limits its use. Six viruses infection in 272 wild capture and artificial breeding Tupaia were investigated in this study. All serum samples were detected for the hepatitis B virus surface antigen, the total antibodies of HCV, hepatitis E virus (HEV), adenovirus (ADV), herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) by ELISA. The results showed that anti-HCV antibody and anti-HEV, ADV, HSV-1 IgG antibodies were negative, only one sample was positive of anti-HSV-2 IgG.. Three samples were positive in the primary ELISA detection of HBV surface antigen, but two pairs of semi-quantitative detection of hepatitis B and further recognized as negative. The results implied that antigen or antibody-positive results appeared in the hepatitis serological test is not accurate enough and confirmation by other virological indicators is necessary. Tupaia breeding herd should be screened for HSV-2 in order to prevent and control the virus infection.
Due to their special phylogenetic position in the Euarchontoglires and close affinity to primates, tree shrews have been proposed as an alternative experimental animal to primates in biomedical research. However, the population genetic structure of tree shrews has largely remained unknown and this has hindered the development of tree shrew breeding and selection. Here we sampled 80 Chinese tree shrews (Tupaia belangeri chinensis) in Kunming, China, and analyzed partial mtDNA control region sequence variation. Based on our samples and two published sequences from northern tree shrews (T. belangeri), we identified 29 substitutions in the mtDNA control region fragment (~ 604 bp) across 82 individuals and defined 13 haplotypes. Seventeen samples were selected for sequencing of the cytochrome b (Cyt b; 1134 bp) gene based on control region sequence variation and were analyzed in combination with 34 published sequences to solidify the phylogenetic pattern obtained from control region data. Overall, tree shrews from Kunming have high genetic diversity and present a remarkable long genetic distance to the two reported northern tree shrews outside China. Our results provide some caution when using tree shrews to establish animal models because of this apparent genetic difference. In addition, the high genetic diversity of Chinese tree shrews inhabiting Kunming suggests that systematic genetic investigations should be conducted before establishing an inbred strain for medical and biological research.
Recent genome studies indicate that tree shrew is in the order or a closest sister of primates, and thus may be one of the best animals to model human diseases. In this paper, we report on a social defeat model of depression in tree shrew (Tupaia belangeri chinensis). Two male tree shrews were housed in a pair-cage consisting of two independent cages separated by a wire mesh partition with a door connecting the two cages. After one week adaptation, the connecting door was opened and a brief fighting occurs between the two male tree shrews and this social conflict session consisted of 1 h direct conflict (fighting) and 23 h indirect influence (e.g. smell, visual cues) per day for 21 days. The defeated tree shrew was considered the subordinate. Compared with naïve animals, subordinate tree shrews at the final week of social conflict session showed alterations in body weight, locomotion, avoidance behavior and urinary cortisol levels. Remarkably, these alterations persisted for over two weeks. We also report on a novel captive conditioning model of learning and memory in tree shrew. An automatic trapping cage was placed in a small closed room with a freely-moving tree shrew. For the first four trials, the tree shrew was not trapped when it entered the cage and ate the bait apple, but it was trapped and kept in the cage for 1 h on the fifth trial. Latency was defined as the time between release of the tree shrew and when it entered the captive cage. Latencies during the five trials indicated adaptation. A test trial 24 h later was used to measure whether the one-trial trapping during the fifth trial could form captive memory. Tree shrews showed much longer trapping latencies in the test trial than the adaptation trials. The N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (0.2 mg/kg, i.p.), known to prevent the formation of memory, did not affect latencies in the adaptation trails, but did block captive memory as it led to much shorter trapping latencies compared to saline treatment in the test trial. These results demonstrate a chronic social defeat model of depression and a novel one-trial captive conditioning model for learning and memory in tree shrews, which are important for mechanism studies of depression, learning, memory, and preclinical evaluation for new antidepressants.
To make Macaca mulatta and Tupaia belangeri as experimental animals for studying functions of opioid and cannabinoid receptors in drug addiction, we examined expression of the opioid and cannabinoid receptors in nervous and immune system of the two animals. We dissected normal adult M. mulatta and T. belangeri, collected tissues of cortex, cerebellum, brain stem, hippocampus, spinal cord, and spleen, and then applied the semi-quantitative PCR and real-time quantitative PCR methods to investigate the mRNA expression levels of the opioid and cannabinoid receptors in these tissues. In M. mulatta, the cannabinoid receptor 1 (CNR1) mRNA was expressed in the all tissues; in contrast, the cannabinoid receptor 2 (CNR2) mRNA was only present in the spleen. The mu opioid receptor (MOPR) was detected in all tissues, and the kappa opioid receptor (KOPR) was found in the cortex, cerebellum, brain stem, and spinal cord, but not in hippocampus and spleen. However, the delta opioid receptor (DOPR) was restrictively expressed in the hippocampus. In T. belangeri, CNR1 and CNR2 were expressed in the five regions of the brain. CNR2, but no CNR1, was also detected in the spleen. MOPR was expressed in all examined tissues, and its expression levels in the brain were higher than that in the spleen. DOPR and KOPR were not found in all tissues. Taken together, the expression profiles of cannabinoid receptors in human being, M. mulatta, T. belangeri, and rat were similar, and the expression patterns of the opioid receptors in M. mulatta were more close to human beings. The opioid and cannabinoid receptors were expressed in the tissues of nervous and immune systems of M. mulatta and T. belangeri, and both animals could be used for studying drug addiction. Macaca mulatta is still the best experimental animal for drug addiction research because it shows very similar expression profiles of these receptors to human beings.
The lack of appropriate animal models that utilizes HIV-1 as the challenge virus is a major impediment to HIV/AIDS research. A major reason underlying the inability of HIV-1 to replicate in nonhuman primate cells is the existence of host antiviral restriction factors. The intrinsic antiviral proteins in host cells are described as restriction factors. The understanding of restriction factors and their mechanism in different primates would undoubtedly facilitate the development of HIV/AIDS animal models. TRIM5α is an important restriction factor and can restrict the infection of several retroviruses including HIV-1 in a species-specific fashion. TRIM5-cyclophilin A (TRIMCyp) gene is an unusual TRIM5 locus found in New World and Old World monkeys. The different TRIMCyp genotypes of four primates (110 samples) including assam macaque (Macaca assamensis), tibetan macaque (M. thibetana), stump-tailed macaque (M. arctoides) and Chinese rhesus macaques (M. mulatta) were studied in this paper. We firstly found that TRIM5-CypA fusion gene exist in M. assamensis. The TRIMCyp of M. assamensis also results from the retrotransposition of CypA pseudogene cDNA into 3'-UTR of TRIM5 gene like TRIMCyp of M. leonina. Moreover, there is an extremely high sequence homology between TRIMCyp genes from M. assamensis and M. leonina. Besides, we also found the G-to-T mutation (G/T) in the 3'splicing site of TRIM5 intron 6, which was identical to M. leonina. These results indicateM. assamensis may also encode TRIMCyp protein like M. leonine, which imply M. assamensis might be infected by HIV-1. Therefore, it is very possible that M. assamensis will be used as a new HIV/AIDS animal model.
Type 2 diabetes mellitus (T2DM) is a metabolic disease with a strong genetic component that is very prevalent in the world. The aim of this study is to investigate the association of a set of six obesity-related genes with the different disease phases of T2DMin a model using middle or aged cynomogus monkeys. A total of 25 male monkeys were used and fed with high-fat diet (15% lard). The disease development and progression of T2DM were monitored through the levels of plasma glucose and lipid. The mRNA expression of 6 genes was evaluated using real-time PCR on monocyte isolated from monkey peripheral blood. The 2-hour plasma glucose levels followed oral glucose tolerance test (OGTT) were (11.06±6.05) mmol/L and (13.12±2.89) mmol/L respectively (P<0.01), and the fasting plasma glucose level was (7.58±1.56) mmol/L (vs controls, P<0.01), indicating that we developed successful the models of pre-diabetic and diabetic disease in the cynomolgus monkey. Of the six tested genes, CDKN2B, IGF2BP2, and FTO genes were significantly up-regulated with disease progression in T2DM. We found that the expression of IGF2BP2 and FTO increased 65.92 and 4.30 folds in the developed T2DM. We conclude that the genes of CDKN2B, IGF2BP2, and FTO can be used as early diagnostic and prognostic biomarkers in type 2 diabetes.
Similar to humans, most of non-human primates also contain the ABO blood group system. In this study, we sought to evaluate the ABO antibody (Ab) levels in monkeys using a modified flow cytometry method (FCM). The standard commercial human A or B-red blood cells (RBCs) were used as target cells. The binding of target cells and anti-A or B blood group Ab in sera of rhesus or cynomolgus monkeys was detected by flow cytometry after adding secondary specific fluorescence-labeled anti-human IgG or IgM Ab. Human healthy blood donor sera were used as controls. The results revealed that, using clear monkey sera, which were pre-absorbed on normal human type O RBCs to remove non-specific anti-human Abs, the modified FCM gave an accurate detection of ABO Ab levels in monkeys. When compared with the results of human sera, the distribution of ABO Ab levels in monkey sera were significantly lower (P<0.05). We concluded that the modified FCM could be used for the detection of monkey ABO Ab levels. The technique and data will be very valuable for the future establishment of ABO-incompatible organ transplant models in non-human primates, which could improve clinical applications.
Schizophrenia is one of the most severe mental disorders with a worldwide incidence of 1%. Previous studies suggested that the brain volumes of the schizophrenia patients were much smaller than the healthy individuals and many schizophrenia susceptible genetic variants have been shown associated with structural brain abnormalities in patients, which is consistent with the neurodevelopmental hypothesis of the etiology of schizophrenia. Recently, the DKK4 gene involved in the Wnt signaling was found to be significantly associated with schizophrenia. To test whether DKK4 is associated with neurodevelopment, we genotyped one DKK4 SNP in 961 healthy Chinese individuals and measured their brain volumes. We found that the SNP was significantly associated with brain volume under both additive and dominant genetic models, providing evidence that schizophrenia susceptible genes could influence brain volume. Our findings support the neurodevelopmental hypothesis of the etiology of schizophrenia.
研究报告
Virological testing and monitoring is a fundamental part of quality control of experimental animals. However, there are few papers regarding the spectrum and status of natural infection in wild tree shrews with human and animal pathogenic viruses. Using enzyme-linked immunosorbent adsorption assay (ELISA), we tested sixty wild tree shrews captured from Qinglong, an outskirt region of Kunming, Yunnan Province, China for eleven viruses, including herpes simplex virus, coxsackie virus, influenza virus, HAV, HBV, HCV, HDV, dengue virus, hemorrhagic fever virus and measles virus. Our results showed that, in the serum samples, 22/60 (36.7%) and 1/60 (1.67%) were antibody positive for herpes simplex virus and coxsackie virus, respectively, and 4/60 (6.7%) were antigen positive for rotavirus in the feces. The remaining species of viruses were negative in these tree shrews. Based on these results, we propose that herpes simplex virus, coxsackie virus and cotavirus should be listed as top priority for routine virological monitoring of tree shrews.