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A neuron-specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

Animal Models and Experimental medicine 2023年第2期6卷 155-167页

作者： Hanxuan Sheng Dan Lu Xiaolong Qi Yahao Ling Jing Li Xu Zhang Wei Dong Wei Chen Shan Gao Xiang Gao Li Zhang Lianfeng Zhang Key Laboratory of Human Disease Comparative Medicine National Health Commission of China(NHC)Institute of Laboratory Animal SciencePeking Union Medical CollegeChinese Academy of Medical SciencesBeijingChina Beijing Engineering Research Center for Experimental Animal Models of human diseases Institute of Laboratory Animal SciencePeking Union Medical CollegeChinese Academy of Medical SciencesBeijingChina

Background:Multiple mitochondrial dysfunction syndromes(MMDS)are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins.This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death.Methods:We generated neuron-specific Isca1 knockout rat(Isca1 flox/flox-NeuN-Cre)using CRISPR-Cas9 technology.The brain structure changes of CKO rats were studied with MRI,and the behavior abnormalities were analyzed through gait analysis and open field tests,Y maze tests and food maze tests.The pathological changes of neurons were analyzed through H&E staining,Nissl staining,and Golgi staining.Mitochondrial damage was assessed by TEM,western blot and ATP assay,and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons.Results:This study established the disease model of MMDS5 in the nervous system for the first time,and found that after Isca1 loss,the rats suffered from developmental retardation,epilepsy,memory impairment,massive neuronal death,reduced number of Nissl bodies and dendritic spines,mitochondrial fragmentation,cristae fracture,reduced content of respiratory chain complex protein,and reduced production of ATP.Isca1 knockout caused neuronal oncosis.Conclusions:This rat model can be used to study the pathogenesis of MMDS.In addition,compared with human MMDS5,the rat model can survive up to 8 weeks of age,effectively extending the window of clinical treatment research,and can be used for the treatment of neurological symptoms in other mitochondrial diseases.

关键词： ISCA1 mitochondrial iron-sulfur cluster MMDS5 neuron oncosis

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Effectiveness and mechanisms of adipose-derived stem cell therapy in animal models of Parkinson's disease:a systematic review and meta-analysis

Effectiveness and mechanisms of adipose-derived stem cell th...

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第十六届中国实验动物科学年会

作者： keya Li Xinyue Li Guiying Shi Xuepei Lei Yiying Huang Lin Bai Chuan Qin Key Laboratory of Human Disease Comparative Medicine Chinese Ministry of HealthBeijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious DiseasesInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciencesand Comparative Medicine CenterPeking Union Medical College

Animal models provide an opportunity to assess the optimal treatment way and the underlying mechanisms of direct clinical application of adipose-derived stem cells(ADSCs).Previous studies have evaluated the effects of primitive and induced ADSCs in animal models of Parkinson’s disease(PD).Here,eight databases were systematically searched for studies on the effects and in vivo changes caused by ADSC intervention.Quality assessment was conducted using a 10-item risk of bias tool.For thesubsequent meta-analysis,study characteristics were extracted and effect sizes were computed.Ten outof 2,324 published articles(n=169 animals)were selected for further meta-analysis.After ADSC therapy,the rotation behavior(10 experiments,n=156 animals) and rotarod performance(3 experiments,n=54 animals) were improved(P <0.00001 and P=0.0003,respectively).The rotation behavior test reflects the functional recovery,which may be due to the neurogenesis from neuronally differentiated ADSCs,resulting in a higher pooled effect size of standard mean difference(SMD)(-2.59;95%Cl,-3.57 to-1.61) when compared to that of primitive cells(-2.18;95% Cl,-3.29 to-1.07).Stratified analyses by different time intervals indicated that ADSC intervention exhibited a long-term effect.Following the transplantation of ADSCs,tyrosine hydroxylase-positive neurons recovered in the lesion area with pooled SMD of 13.36[6.85,19.86].Transplantation of ADSCs is a therapeutic option that shows long-lasting effects in animal models of PD.The potential mechanisms of ADSCs involve neurogenesis and neuroprotective effects.The standardized induction of neural form of transplanted ADSCs can lead to a future application in clinical practice.

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Summary of animal models of myelodysplastic syndrome

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Animal Models and Experimental medicine 2021年第1期4卷 71-76页

作者： Weisha Li Mengyuan Li Xingjiu Yang Wenlong Zhang Lin Cao Ran Gao NHC Key Laboratory of Human Disease Comparative Medicine BeijingChina Beijing Engineering Research Center for Experimental Animal Models of human Critical diseases BeijingChina Institute of laboratory Animal Sciences Chinese Academy of Medical Sciences(CAMS)BeijingChina comparative medicine Center Peking Union Medical College(PUMC)BeijingChina Beijing Tongren Hospital Affiliated to Capital Medical University BeijingChina

Myelodysplastic syndrome(MDS)is a malignant tumor of the hematological system characterized by long-term,progressive refractory hemocytopenia.In addition,the risk of leukemia is high,and once it develops,the course of acute leukemia is short with poor curative effect.Animal models are powerful tools for studying human diseases and are highly effective preclinical platforms.Animal models of MDS can accurately show genetic aberrations and hematopoietic clone phenotypes with similar cellular features(such as impaired differentiation and increased apoptosis),and symptoms can be used to assess existing treatments.Animal models are also helpful for understanding the pathogenesis of MDS and its relationship with acute leukemia,which helps with the identification of candidate genes related to the MDS phenotype.This review summarizes the current status of animal models used to research myelodysplastic syndrome(MDS).

关键词： animal models Leukemia myelodysplastic syndrome(MDS)

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SARS-CoV-2 infection aggravates chronic comorbidities of cardiovascular diseases and diabetes in mice

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Animal Models and Experimental medicine 2021年第1期4卷 2-15页

作者： Yuanwu Ma Dan Lu Linlin Bao Yajin Qu Jiangning Liu Xiaolong Qi Lei Yu Xu Zhang Feifei Qi Qi Lv Yunpeng Liu Xudong Shi Caixian Sun Jing Li Jie Wang Yunlin Han Kai Gao Wei Dong Ning Liu Shan Gao Jing Xue Qiang Wei Sidan Pan Hong Gao Lianfeng Zhang Chuan Qin Key Laboratory of Human Disease Comparative Medicine National Health Commission of China(NHC)Institute of Laboratory Animal SciencePeking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina Beijing Engineering Research Center for Experimental Animal Models of human Critical diseases Institute of Laboratory Animal SciencePeking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina

Background:Cardiovascular diseases(CVDs)and diabetes mellitus(DM)are top two chronic comorbidities that increase the severity and mortality of COVID-19.However,how SARS-CoV-2 alters the progression of chronic diseases remain unclear.Methods:We used adenovirus to deliver h-ACE2 to lung to enable SARS-CoV-2 infection in mice.SARS-CoV-2’s impacts on pathogenesis of chronic diseases were studied through histopathological,virologic and molecular biology analysis.Results:Pre-existing CVDs resulted in viral invasion,ROS elevation and activation of apoptosis pathways contribute myocardial injury during SARS-CoV-2 infection.Viral infection increased fasting blood glucose and reduced insulin response in DM model.Bone mineral density decreased shortly after infection,which associated with impaired PI3K/AKT/mTOR signaling.Conclusion:We established mouse models mimicked the complex pathological symptoms of COVID-19 patients with chronic diseases.Pre-existing diseases could impair the inflammatory responses to SARS-CoV-2 infection,which further aggravated the pre-existing diseases.This work provided valuable information to better understand the interplay between the primary diseases and SARS-CoV-2 infection.

关键词： Cardiovascular disease COVID-19 diabetes mellitus mouse model SARS-CoV-2

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Current state of research on non-human primate models of Alzheimer’s disease

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Animal Models and Experimental medicine 2019年第4期2卷 227-238页

作者： Hong-Wei Li Ling Zhang Chuan Qin NHC Key Laboratory of Human Disease Comparative Medicine Peking Union Medical College(PUMC)BeijingChina key laboratory of human diseases Animal Model State Administration of Traditional Chinese MedicinePeking Union Medical College(PUMC)BeijingChina The Institute of laboratory Animal Sciences Chinese Academy of Medical Sciences(CAMS)Peking Union Medical College(PUMC)BeijingChina Ministry of Health Comparative Medicine CenterPeking Union Medical College(PUMC)BeijingChina

With the increasingly serious aging of the global population, dementia has already become a severe clinical challenge on a global scale. Dementia caused by Alzheimer’s disease(AD) is the most common form of dementia observed in the elderly, but its pathogenetic mechanism has still not been fully elucidated. Furthermore, no effective treatment strategy has been developed to date, despite considerable efforts. This can be mainly attributed to the paucity of animal models of AD that are sufficiently similar to humans. Among the presently established animal models, non-human primates share the closest relationship with humans, and their neural anatomy and neurobiology share highly similar characteristics with those of humans. Thus, there is no doubt that these play an irreplaceable role in AD research. Considering this, the present literature on non-human primate models of AD was reviewed to provide a theoretical basis for future research.

关键词： Alzheimer's disease animal models genetic modification non-human primates

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A broadly neutralizing human monoclonal antibody against the hemagglutinin of avian influenza virus H7N9

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Chinese Medical Journal 2022年第7期135卷 799-805页

作者： Jingxin Li Li Zhang Linlin Bao Yuxiao Wang Lin Qiu Jialei Hu Rong Tang Huiyan Yu Jun Shan Yan Li Chuan Qin Fengcai Zhu Department for Vaccine Clinical Evaluation NHC Key Laboratory of Enteric Pathogenic MicrobiologyJlangsu Provincial Center for Diseases Control and PreventionNanjingJiangsu 210009China Institute of laboratory Animal Science Chinese Academy of Medical Sciences(CAMS)&Comparative Medicine CenterPeking Union Medical Collage(PUMC)Key Laboratory of Human Disease Comparative MedicineMinistry of HealthBeijing Key Laboratory for Animal Models of Emerging and Reemerging Infectious DiseasesBeijing 100101China Department of Public Health Southeast UniversityNanjingJiangsu 210009China Shanghai Institute for Biological Sciences Chinese Academy of SciencesShanghai 200031China

Background:The new emerging avian influenza A H7N9 virus,causing severe human infection with a mortality rate of around 41%.This study aims to provide a novel treatment option for the prevention and control of H7N9.Methods:H7 hemagglutinin(HA)-specific B cells were isolated from peripheral blood plasma cells of the patients previously infected by H7N9 in Jiangsu Province,China.The human monoclonal antibodies(mAbs)were generated by amplification and cloning of these HA-specific B cells.First,all human mAbs were screened for binding activity by enzyme-linked immunosorbent assay.Then,those mAbs,exhibiting potent affinity to recognize H7 HAs were further evaluated by hemagglutination-inhibiting(HAI)and microneutralizationin vitro assays.Finally,the lead mAb candidate was selected and tested against the lethal challenge of the H7N9 virus using murine models.Results:The mAb 6-137 was able to recognize a panel of H7 HAs with high affinity but not HA of other subtypes,including H1N1 and H3N2.The mAb 6-137 can efficiently inhibit the HA activity in the inactivated H7N9 virus and neutralize 100 tissue culture infectious dose 50(TCID_(50))of H7N9 virus(influenza A/Nanjing/1/2013)invitro,with neutralizing activity as low as 78 ng/mL.In addition,the mAb 6-137 protected the mice against the lethal challenge of H7N9 prophylactically and therapeutically.Conclusion:The mAb 6-137 could be an effective antibody as a prophylactic or therapeutic biological treatment for the H7N9 exposure or infection.

关键词： Avian influenza H7N9 Monoclonal antibody Neutralizing activity

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Dhcr24 activates the PI3K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice

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Animal Models and Experimental medicine 2018年第1期1卷 40-52页

作者： Wei Dong Fei-fei Guan Xu Zhang Shan Gao Ning Liu Wei Chen Lian-feng Zhang Dan Lu Key Laboratory of Human Disease Comparative Medicine NHFPC Institute of Laboratory Animal Science Chinese Academy of Medical Sciences & Comparative Medical Center Peking Union Medical College

Background: 24-dehydrocholesterol reductase(Dhcr24) catalyzes the last step of cholesterol biosynthesis, which is required for normal development and antiapoptotic activities of tissues. We found that Dhcr24 expression decreased in the cTnTR141 Wdilated cardiomyopathy(DCM) transgenic mice. Therefore, we tested whether rescued expression of Dhcr24 could prevent the development of DCM and its possible mechanism.Methods: Heart tissue specific transgenic overexpression mice of Dhcr24 was generated, then was crossed to c TnTR141 Wmouse to obtain the double transgenic mouse(DTG). The phenotypes were demonstrated by the survival, cardiac geometry and function analysis, as well as microstructural and ultrastructural observations based on echocardiography and histology examination. The pathway and apoptosis were analysed by western blotting and TUNEL assay in vivo and in vitro.Results: We find that Dhcr24 decreased in hearts tissues of cTnTR141 Wand LMNAE82 KDCM mice. The transgenic overexpression of Dhcr24 significantly improves DCM phenotypes in cTnTR141 Wmice, and activates PI3K/Akt/HKII pathway, followed by a reduction of the translocation of Bax and release of cytochrome c, caspase-9 and caspase-3 activation and myocyte apoptosis. Knockdown the expression of Dhcr24 reduces the activation of PI3K/Akt/HKII pathway and inhibition of the mitochondrial-dependent apoptosis. The anti-apoptotic effect of Dhcr24 could be completely removed by the inhibition of PI3K pathway and partly removed by the HKII inhibitor in H9c2 cell line.Conclusion: Compensatory expression of Dhcr24 protect against DCM through activated PI3K/Akt/HKII pathway and reduce Bax translocation. This is the first investigation for the molecular mechanism of Dhcr24 participate in development of DCM.

关键词： apoptosis Dhcr24 dilated cardiomyopathy gene expression and regulation

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Sequential infection with H1N1 and SARS-CoV-2 aggravated COVID-19 pathogenesis in a mammalian model, and covaccination as an effective method of prevention of COVID-19 and influenza

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Signal Transduction and Targeted Therapy 2021年第6期6卷 1876-1883页

作者： Linlin Bao Wei Deng Feifei Qi Qi Lv Zhiqi Song Jiangning Liu Hong Gao Qiang Wei Pin Yu Yanfeng Xu Yajin Qu Fengdi Li Jing Xue Shuran Gong Mingya Liu Guanpeng Wang Shunyi Wang Binbin Zhao Bin Cong Chuan Qin Beijing key laboratory for Animal Models of Emerging and Remerging Infectious diseases NHC Key Laboratory of Human Disease Comparative MedicineInstitute of Laboratory Animal ScienceChinese Academy of Medical Sciences and Comparative Medicine CenterPeking Union Medical CollegeBeijingChina Hebei Medical University ShijiazhuangChina

Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus,leading to more serious respiratory diseases during this winter.However,the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear.Using a mammalian model,sequential infection was performed in ferrets and in K18-MCE2 mice,with SARS-CoV-2 infection following H1N1.We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19,and enhanced pulmonary damage,but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets.Moreover,mortality was increased in sequentially infected mice compared with single-infection mice.Compared with singlevaccine inoculation,co-inoculation of PiCoVacc(a SARS-CoV-2 vaccine)and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses.Combined immunization effectively protected K18-MCE2 mice against both H1N1 and SARS-CoV-2 infection.Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2,which together notably enhanced pneumonia in ferrets and mice,as well as demonstrated that simultaneous vaccination against HINT and SARS-CoV-2 may be an effective prevention strategy for the coming winter.

关键词： prevention H1N1 influenza

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TRDMT1 exhibited protective effects against LPS-induced inflammation in rats through TLR4-NF-κB/MAPK-TNF-αpathway

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Animal Models and Experimental medicine 2022年第2期5卷 172-182页

作者： Zhengguang Li Xiaolong Qi Xu Zhang Lei Yu Lijuan Gao Weining Kong Wei Chen Wei Dong Lijun Luo Dan Lu Lianfeng Zhang Yuanwu Ma Key Laboratory of Human Disease Comparative Medicine National Health Commission of China(NHC)Institute of Laboratory Animal ScienceChinese Academy of Medical SciencesPeking Union Medicine CollegeBeijingChina National human diseases Animal Model Resource Center and Beijing Engineering Research Center for Experimental Animal Models of human Critical diseases Institute of Laboratory Animal SciencePeking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina Neuroscience Center Chinese Academy of Medical SciencesBeijingChina

Background:Inflammation is a complex physiological and pathological process.Although many types of inflammation are well characterized,their physiological func-tions are largely unknown.tRNA aspartic acid methyltransferase 1(TRDMT1)has been implicated as a stress-related protein,but its intrinsic biological role is unclear.Methods:We constructed a Trdmt1 knockout rat and adopted the LPS-induced sepsis model.Survival curve,histopathological examination,expression of inflammatory fac-tors,and protein level of TLR4 pathway were analyzed.Results:Trdmt1 deletion had no obvious impact on development and growth.Trdmt1 de-letion slightly increased the mortality during aging.Our data showed that Trdmt1 strongly responded in LPS-treated rats,and Trdmt1 knockout rats were vulnerable to LPS treat-ment with declined survival rate.We also observed more aggravated tissue damage and more cumulative functional cell degeneration in LPS-treated knockout rats compared with control rats.Further studies showed upregulated TNF-αlevel in liver,spleen,lung,and serum tissues,which may be explained by enhanced p65 and p38 phosphorylation.Conclusions:Our data demonstrated that Trdmt1 plays a protective role in inflamma-tion by regulating the TLR4-NF-κB/MAPK-TNF-αpathway.This work provides useful information to understand the TRDMT1 function in inflammation.

关键词： inflammation knockout rat TLR4 pathway TNF-α Trdmt1

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GTPase-activating protein TBC1D5 coordinates with retromer to constrain synaptic growth by inhibiting BMP signaling

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Journal of Genetics and Genomics 2023年第3期50卷 163-177页

作者： Xiu Zhou Guangming Gan Yichen Sun Mengzhu Ou Junhua Geng Jing Wang Xi Yang Shu Huang Da Jia Wei Xie Haihuai He State key laboratory of Biotherapy Department of NeurosurgeryWest China HospitalSichuan UniversityChengduSichuan 610041China The key laboratory of Developmental Genes and human disease(MOE) School of Life Science and TechnologySoutheast UniversityNanjingJiangsu 210096China The key laboratory of Developmental Genes and human disease(MOE) School of MedicineSoutheast UniversityNanjingJiangsu 210009China key laboratory of Birth Defects and Related diseases of Women and Children Department of PediatricsWest China Second University HospitalState Key Laboratory of BiotherapySichuan UniversityChengduSichuan 610041China

Formation and plasticity of neural circuits rely on precise regulation of synaptic growth.At Drosophila neuromuscular junction(NMJ),Bone Morphogenetic Protein(BMP)signaling is critical for many aspects of synapse formation and function.The evolutionarily conserved retromer complex and its associated GTPase-activating protein TBC1D5 are critical regulators of membrane trafficking and cellular signaling.However,their functions in regulating the formation of NMJ are less understood.Here,we report that TBC1D5 is required for inhibition of synaptic growth,and loss of TBC1D5 leads to abnormal presynaptic terminal development,including excessive satellite boutons and branch formation.Ultrastructure analysis reveals that the size of synaptic vesicles and the density of subsynaptic reticulum are increased in TBC1D5mutant boutons.Disruption of interactions of TBC1D5 with Rab7 and retromer phenocopies the loss of TBC1D5.Unexpectedly,we find that TBC1D5 is functionally linked to Rab6,in addition to Rab7,to regulate synaptic growth.Mechanistically,we show that loss of TBC1D5 leads to upregulated BMP signaling by increasing the protein level of BMP type Ⅱ receptor Wishful Thinking(Wit)at NMJ.Overall,our data establish that TBC1D5 in coordination with retromer constrains synaptic growth by regulating Rab7 activity,which negatively regulates BMP signaling through inhibiting Wit level.

关键词： TBC1D5 NMJ Synaptic growth Retromer BMP signaling

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