Increased expression of matrix metalloproteinase-1(MMP-1)has been observed in the lesions of atherosclerosis and aneurysms;however,it is not fully understood whether macrophage-derived MMP-1 affects these diseases.To ...Increased expression of matrix metalloproteinase-1(MMP-1)has been observed in the lesions of atherosclerosis and aneurysms;however,it is not fully understood whether macrophage-derived MMP-1 affects these diseases.To investigate whether macrophage-derived MMP-1 participates in the development of vascular diseases,we generated transgenic(Tg)rabbits expressing human MMP-1 in the monocyte/macrophage lineage under the control of the human scavenger receptor enhancer/promoter.Tg rabbits exhibited no visible abnormalities throughout their bodies.Western blotting analysis revealed that the amount of MMP-1 proteins in the conditioned media secreted from peritoneal macrophages of Tg rabbits was up to 3-fold higher than that in non-Tg rabbits.For the first experiment,Tg and non-Tg rabbits were fed a cholesterol diet for 16 weeks,and aortic and coronary atherosclerosis were evaluated.The gross lesion area of aortic atherosclerosis in Tg rabbits was not significantly different from that in non-Tg rabbits,but Tg rabbits had marked destruction of the medial elastic lamina of the aortic lesions on microscopic examination.For the second experiment,we generated aortic aneurysms by incubating with elastase.Compared with non-Tg rabbits,Tg rabbits exhibited a significantly greater aortic dilation.Increased macrophage-derived MMP-1 led to increased medial destruction in both aortic atherosclerosis and aneurysms.These results demonstrate that MMP-1 plays a different role in the pathogenesis of atherosclerosis and aneurysms.展开更多
Animal models are increasingly gaining values by cross-comparisons of response or resistance to clinical agents used for patients.However,many disease mechanisms and drug effects generated from animal models are not t...Animal models are increasingly gaining values by cross-comparisons of response or resistance to clinical agents used for patients.However,many disease mechanisms and drug effects generated from animal models are not transferable to human.To address these issues,we developed SysFinder(http://lifecenter.sgst.cn/SysFinder),a platform for scientists to find appropriate animal models for translational research.SysFinder offers a "topic-centered" approach for systematic comparisons of human genes,whose functions are involved in a specific scientific topic,to the corresponding homologous genes of animal models.Scientific topic can be a certain disease,drug,gene function or biological pathway.SysFinder calculates multi-level similarity indexes to evaluate the similarities between human and animal models in specified scientific topics.Meanwhile,SysFinder offers species-specific information to investigate the differences in molecular mechanisms between humans and animal models.Furthermore,SysFinder provides a userfriendly platform for determination of short guide RNAs(sgRNAs) and homology arms to design a new animal model.Case studies illustrate the ability of SysFinder in helping experimental scientists.SysFinder is a useful platform for experimental scientists to carry out their research in the human molecular mechanisms.展开更多
Gene editing nucleases(GENs),represented by CRISPR/Cas9,have become major tools in biomedical research and offer potential cures for many human diseases.Gene editing therapy(GETx)studies in animal models targeting gen...Gene editing nucleases(GENs),represented by CRISPR/Cas9,have become major tools in biomedical research and offer potential cures for many human diseases.Gene editing therapy(GETx)studies in animal models targeting genes such as proprotein convertase subtilisin/kexin type 9(PCSK9),apolipoprotein C3(APOC3),angiopoietin Like 3(ANGPTL3)and inducible degrader of the low-density lipoprotein receptor(IDOL)have demonstrated the benefits and advantages of GETx in managing atherosclerosis.Here we present our views on this brand new therapeutic option for cardiovascular diseases(CVD).展开更多
The rabbit has been recognized as a valuable model in various biomedical and biological research fields because of its intermediate size and phylogenetic proximity to primates.However,the technology for precise genome...The rabbit has been recognized as a valuable model in various biomedical and biological research fields because of its intermediate size and phylogenetic proximity to primates.However,the technology for precise genome manipulations in rabbit has been stalled for decades,severely limiting its applications in biomedical research.Novel genome editing technologies,especially CRISPR/Cas9,have remarkably enhanced precise genome manipulation in rabbits,and shown their superiority and promise for generating rabbit models of human genetic diseases.In this review,we summarize the brief history of transgenic rabbit technology and the development of novel genome editing technologies in rabbits.展开更多
基金supported in part by research grants from JSPS KAKENHI(JP26460486 to MN and JP15H04718 to JF)NIH grants(R01HL117491and RO1HL129778 to YEC)
文摘Increased expression of matrix metalloproteinase-1(MMP-1)has been observed in the lesions of atherosclerosis and aneurysms;however,it is not fully understood whether macrophage-derived MMP-1 affects these diseases.To investigate whether macrophage-derived MMP-1 participates in the development of vascular diseases,we generated transgenic(Tg)rabbits expressing human MMP-1 in the monocyte/macrophage lineage under the control of the human scavenger receptor enhancer/promoter.Tg rabbits exhibited no visible abnormalities throughout their bodies.Western blotting analysis revealed that the amount of MMP-1 proteins in the conditioned media secreted from peritoneal macrophages of Tg rabbits was up to 3-fold higher than that in non-Tg rabbits.For the first experiment,Tg and non-Tg rabbits were fed a cholesterol diet for 16 weeks,and aortic and coronary atherosclerosis were evaluated.The gross lesion area of aortic atherosclerosis in Tg rabbits was not significantly different from that in non-Tg rabbits,but Tg rabbits had marked destruction of the medial elastic lamina of the aortic lesions on microscopic examination.For the second experiment,we generated aortic aneurysms by incubating with elastase.Compared with non-Tg rabbits,Tg rabbits exhibited a significantly greater aortic dilation.Increased macrophage-derived MMP-1 led to increased medial destruction in both aortic atherosclerosis and aneurysms.These results demonstrate that MMP-1 plays a different role in the pathogenesis of atherosclerosis and aneurysms.
基金supported by the National High Technology Research and Development Program of China(No.2015AA020104)the National Key Research and Development Program on Precision Medicine(No.2016YFC0901700)+6 种基金the National Basic Research Program of China(Nos.2011CB910204,2011CB510102,and 2010CB529200)the National Key Technology Support Program (No.2013BA1101B09)the National Key Scientific Instrument and Equipment Development Project(No.2012YQ03026108)the National Grand Program on Key Infectious Diseases(No. 2015ZX10004801)the Medical-Engineering Cross Project of Shanghai Jiao Tong University(No.YG2016MS33)the Youth Innovation Promotion Association CASthe National Institutes of Health grants(Nos.R01HL117491 and R01HL129778 to Y.E.C)
文摘Animal models are increasingly gaining values by cross-comparisons of response or resistance to clinical agents used for patients.However,many disease mechanisms and drug effects generated from animal models are not transferable to human.To address these issues,we developed SysFinder(http://lifecenter.sgst.cn/SysFinder),a platform for scientists to find appropriate animal models for translational research.SysFinder offers a "topic-centered" approach for systematic comparisons of human genes,whose functions are involved in a specific scientific topic,to the corresponding homologous genes of animal models.Scientific topic can be a certain disease,drug,gene function or biological pathway.SysFinder calculates multi-level similarity indexes to evaluate the similarities between human and animal models in specified scientific topics.Meanwhile,SysFinder offers species-specific information to investigate the differences in molecular mechanisms between humans and animal models.Furthermore,SysFinder provides a userfriendly platform for determination of short guide RNAs(sgRNAs) and homology arms to design a new animal model.Case studies illustrate the ability of SysFinder in helping experimental scientists.SysFinder is a useful platform for experimental scientists to carry out their research in the human molecular mechanisms.
文摘Gene editing nucleases(GENs),represented by CRISPR/Cas9,have become major tools in biomedical research and offer potential cures for many human diseases.Gene editing therapy(GETx)studies in animal models targeting genes such as proprotein convertase subtilisin/kexin type 9(PCSK9),apolipoprotein C3(APOC3),angiopoietin Like 3(ANGPTL3)and inducible degrader of the low-density lipoprotein receptor(IDOL)have demonstrated the benefits and advantages of GETx in managing atherosclerosis.Here we present our views on this brand new therapeutic option for cardiovascular diseases(CVD).
文摘The rabbit has been recognized as a valuable model in various biomedical and biological research fields because of its intermediate size and phylogenetic proximity to primates.However,the technology for precise genome manipulations in rabbit has been stalled for decades,severely limiting its applications in biomedical research.Novel genome editing technologies,especially CRISPR/Cas9,have remarkably enhanced precise genome manipulation in rabbits,and shown their superiority and promise for generating rabbit models of human genetic diseases.In this review,we summarize the brief history of transgenic rabbit technology and the development of novel genome editing technologies in rabbits.