[英语新闻]人性化“的老鼠，可以提供更好的药物对人类的毒

StephenW

人性化“的老鼠，可以提供更好的药物对人类的毒性评估”
http://www.nature.com/news/2011/110711/full/news.2011.409.html?WT.ec_id=NEWS-20110712
Humanized' mice could provide better assessment of drugs' toxicity for humans.        

                                                    Marian Turner                                               

        
                                                                                        Mice metabolize some drugs differently from humans — unless they have a human liver.Redmond Durrell / Alamy
The unique physiology of the human liver means that the toxicity of some candidate drugs is not picked up during preclinical tests in animals. But mice implanted with miniature human livers can mimic the ways in which the human body breaks down chemical compounds, to help spot potential problems before drugs are tested in humans.
A team led by Sangeeta Bhatia, a biomedical engineer at the Massachusetts Institute of Technology in Cambridge, made 20-millimetre-long artificial human livers and implanted them into otherwise normal mice. The researchers report today in  Proceedings of the National Academy of Sciences1, that the mice showed metabolism characteristic of the human liver for weeks after implantation.
"The key technique is that we make stable liver implants in the laboratory first," says biomedical engineer Alice Chen, an author on the study. The researchers combined human liver cells (hepatocytes) that carry out the liver's metabolic functions, with mouse fibroblast cells and human liver endothelial cells, which provide chemical signals the hepatocytes need to function. They encased the cell packages in a plastic scaffold and implanted them into mice.
When they gave the mice drugs that humans and mice break down differently, the mice produced the same breakdown products (metabolites) and showed the same metabolic interactions between drugs as a human would. The authors hope that the new technology will make drug development safer and less costly, by spotting toxicities before a drug gets to clinical trials.
   Faster process "The implants are still a long way from being a liver, so the human metabolism is remarkable," says immunologist James Di Santo at the Pasteur Institute in Paris, who was not involved in the study. But he says these humanized mice might be limited to assessing certain classes of drugs — such as those that are only, or very differently, metabolized by human hepatocytes. The new implants only contain half a million human liver cells, compared to the tens of millions of cells in a mouse liver, so in some cases the mouse cell metabolism might mask the human metabolites that the system is designed to reveal.

Scientists have previously made mice with a greater proportion of human liver cells by injecting human cells into mice with damaged livers and waiting for the human cells to repair the injury. But it takes months for these 'chimeric' livers to form, compared with the 1-2 weeks Bhatia's team need to make their artificial livers. "Chimeras are also highly variable, and it's hard to tell how many of the human cells have proper liver metabolism," says Chen.
Another feature of the implants is that they are not immediately attacked by the mouse immune system. "We can tune the pore size of the polymer so that the mouse immune cells don't have easy access to the human cells inside the implant," says Chen. Because the artificial livers aren't rapidly rejected, scientists can implant them into any mouse strain, and still have weeks to follow their function, whereas chimeric livers can only be made in immunodeficient mice.
For Alexander Ploss, a virologist at Rockefeller University in New York, this means that the implants might be useful not only for drug testing but for studying human diseases. He sees the implanted mice as a toolbox — one into which he wants to add the nuts and bolts of the human immune system. His team recently generated the first non-primate animal model of infection by hepatitis C virus, which infects liver cells, by making mice with humanized immune systems2. "By implanting humanized livers into humanized immune system mice, we could follow hepatitis viruses or malaria parasites interacting with immune cells and the liver at the same time," Ploss says.





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StephenW

谷歌翻译，不是100％准确，仅供参考使用。

人体肝脏的独特生理意味着一些候选药物的毒性，不回升过程中，在临床前动物试验。但小鼠植入微型人类肝脏可以模仿人体的化合物向下突破的方法，使药物在人体试验之前，以帮助发现潜在的问题。

交给Sangeeta巴蒂亚，在剑桥的麻省理工学院的生物医学工程师，领导的一个研究小组提出了20毫米长的人造人体肝脏植入到其他正常小鼠。研究人员报告Sciences1国家科学院学报“，今天在小鼠表现出周后植入人体肝脏的代谢特点。

“的关键技术是生物医学工程师陈翘，对研究报告的作者说，”我们在实验室中稳定的肝脏植入。研究人员结合开展肝脏的代谢功能，与小鼠成纤维细胞和人体肝脏血管内皮细胞，肝细胞所需要的功能提供的化学信号的人类肝细胞（肝细胞）。它们装在一个塑料支架的细胞包和植入小鼠。

当他们给人类和小鼠打破不同药物的小鼠，小鼠产生了相同的分解产物（代谢物）和相同的代谢药物之间的相互作用表现为一个人会。作者希望，新技术将使药物开发更安全，成本更低，通过发现毒性反应，一种药物进入临床试验之前，。
更快的过程

“植入物仍然是一个从一个肝脏很长的路要走，因此，人体新陈代谢是显着的的，说：”在巴黎的巴斯德研究所，谁没有参与这项研究的免疫学家詹姆斯迪桑托。但是他说，这些人性化的小鼠可能是有限的，以评估某些类别的药物 - 如那些只，或非常不同，人类肝细胞代谢。新的植入物，包含五十万人体肝脏细胞相比，数十数百万个细胞在小鼠肝，所以在某些情况下小鼠细胞代谢可能掩盖了该系统是旨在揭示人类的代谢产物，。

科学家们以前作出更大的人类细胞注射到肝脏受损的小鼠和等待人体细胞修复损伤的比例与人类肝细胞的小鼠。但这些“嵌合体的肝脏个月的形式相比，Bhatia的团队需要，使他们的人工肝脏的1-2周。 “嵌合体也充满变数，这很难说，人体细胞有多少人有正确的肝脏代谢，”他说。

植入的另一个特点是，他们不会立即小鼠免疫系统的攻击。 “我们可以调整的聚合物的孔径，使小鼠免疫细胞不容易进入人体细胞内植入，”他说。由于人工肝脏不能迅速拒绝，科学家们可以植入任何小鼠品系，仍然有周，按照其功能，而嵌合体肝脏只能在免疫缺陷小鼠。

亚历山大PLOSS，在纽约洛克菲勒大学的病毒学家，这意味着植入可能，不仅可以用于药物测试，但研究人类疾病的有用。他认为作为一个工具箱植入小鼠 - 之一，他希望能到增加人体免疫系统的螺母和螺栓。他的研究小组最近生成的第一个非灵长类动物感染丙型肝炎病毒感染肝细胞，模型与人性化的免疫systems2小鼠。 “通过人性化的肝脏植入人性化的免疫系统小鼠，我们可以按照肝炎病毒或疟疾寄生虫与免疫细胞和肝脏同时交互，PLOSS说。”