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发表于 2006-1-18 19:09:13
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http://boinc.equn.com/rosetta/rah_medical_relevance.htm
Disease Related Research
Rosetta有关疾病的研究
Comments from David Baker 来自David Baker的介绍
My research group is involved both in fundamental methods development research and in trying to fight disease more directly. Most of the information on this site focuses on basic research, but I thought you might be interested in hearing about some of the disease related work we are doing that you will be contributing to at Rosetta@home.
我们主要有两个研究目标:1.做有关发展基本预测方法的研究;2.尝试更直接更快捷地找到抵御重大疾病的方法.本站的内容大多都是介绍Rosetta的工作流程和基础研究的.但我想,您可能对现实一点的问题更感兴趣.比如Rosetta怎样找到有效抗击疾病的方法等.了解下文将有助您了解Rosetta的工作方向和它所发挥的作用.
Malaria: We are part of a collaborative project headed by Austin Burt at Imperial College in London that is one of the Gates Foundation "Grand Challenge Projects in Global Health". Malaria is caused by a parasite that spends part of its life cycle inside the mosquito, and is passed along to humans by mosquito bites. The idea behind the project is to make mosquitoes resistant to the parasite by eliminating genes required in the mosquito for the parasite to live. Our part of the project is to use our computer based design methods (ROSETTA) to engineer new enzymes that will specifically target and inactivate these genes.
对疟疾的研究是由英国Imperial大学的Austin Burt发起的"Grand Challenge Projects in Global Health"项目的研究板块之一.此项目是由Gates基金成立的.疟疾的引起来源于一种在蚊子体内寄生的虫子.这些可恶的寄生虫通过蚊子对我们的叮咬跑到了人类的血液里面.而这种寄生虫在蚊子体内的生存依赖的就是蚊子的其中某几条条基因.本项目的意义和目的就是要从蚊子的DNA里把那条基因”去掉”.通过Rosetta,我们可以得到一种新的酶来使这类为寄生虫所依靠的基因被”封存起来”,阻止他们发挥效能.
Anthrax: We are using ROSETTA to help John Collier's research group at Harvard build models of anthrax toxin that should contribute to the development of treatments. You can read the abstract of a paper describing some of this work at http://www.pnas.org/cgi/content/abstract/102/45/16409.
John Collier的科研小组正利用Rosetta来帮助建立炭疽毒素的模型.研究成果将捐献给公共医疗体系.有关于Rosetta在炭疽方面的研究进展的概述可在http://www.pnas.org/cgi/content/abstract/102/45/16409页面得知.
HIV: One of the reasons that HIV is such a deadly virus is that it has evolved to trick the immune system. We are collaborating with researchers in Seattle and at the NIH to try to develop a vaccine for HIV. Our role in this project is central--we are using ROSETTA to design small proteins that display the small number of critical regions of the HIV coat protein in a way that the immune system can easily recognize and generate antibodies to. Our goal is to create small stable protein vaccines that can be made very cheaply and shipped all over the world.
获得性人体免疫缺陷病毒(HIV或AIDS)为什么那么致命和骇人听闻?是因为它们能骗过人类的免疫系统,使人体彻底失去保护.在西雅图和NIH(美国国家卫生研究所),我们与研究员们正共同研制HIV的疫苗.我们利用Rosetta来设计一种蛋白质.从而找出HIV病毒表层蛋白质的结构.那样我们就可以找出对付HIV的方法了.本项目的目标是制造出一些功效稳定而且价格低廉的疫苗,然后把疫苗推广到全世界!
Other viruses: We have been collaborating with Pam Bjorkman's laboratory at Cal Tech to use the ROSETTA protein-protein docking methodology to build models of herpes simplex virus proteins in complex with human proteins.
其他的疾病研究项目通过Rosetta来制作相应病毒或细菌的蛋白质模型来找到对付这些疾病的有效方法.例如与Pam Bjorkman的实验室合作的研究员们通过Rosetta来构造疱疹病毒蛋白质的模型.通过疱疹病毒蛋白质与人类细胞蛋白质的复合体来做相关的研究.
Alzheimer's disease: Alzheimer's and many other diseases are likely to be caused by aberrant protein folding in which proteins form large aggregated structures called amyloids rather than folding up into their normal biologically active states. A big advance was made recently by David Eisenberg's research group at UCLA in solving the first structure of an amyloid. We are collaborating with their research group to use the structure to predict which parts of proteins are likely to form amyloids, which will be a first step to blocking amyloid formation and hopefully disease.
阿尔茨海默氏症的起因和很多疾病的一样都是由淀粉蛋白质的异常折叠引起的. 最近,David Eisenberg的研究小组在这一问题研究上取得了很大的进展.他们成功地解析了一个淀粉体的结构.我们正与他们合作,预测与淀粉体蛋白质结构相似的其他蛋白质.这将是我们向蛋白质编队化迈下的第一步.
Cancer: Cancer can be caused by mutations in key genes that disrupt normal cellular control processes. We are developing methods for cutting DNA at specific sites in the genome, and we will be targeting sites that are implicated in cancer. After these sites are cut, they should be repaired by the cell using a second, unmutated copy of the gene and the cell should no longer be cancerous. This is a very specific form of gene therapy that, if successful, will circumvent one the main objections to current gene therapy methods; namely, current methods insert the unmutated copy of a gene randomly into the genome, and if the insertion point happens to be near an oncogene, the gene therapy will cure one disease but cause another. Because our methods will target specific sites instead of random sites, they should avoid this pitfall.
癌症可能由某些关键基因的突变引起,而这直接破坏了动物体细胞的正常运作.我们正试图寻找能从DNA中准确找到引发基因突变的诱因.找到这些基因片段后把它们除掉.细胞会自动”把备份基因信息补上去”,完成修复工作.这些细胞便不再是癌细胞了.这种基因疗法是非常非常精确的.如果成功,现行的所有基因疗法将”报废”.现在的基因疗法是将正常的基因备份随机的加入到基因组中.如果切入点不对,疾病仍然可能发生.通过Rosetta研究出来的方法可以避免这一弊端.我们可以将正常的基因片段放入并取代病灶片断.
Prostate Cancer: The androgen receptor (AR) binds testosterone and is responsible for normal male development. When the AR becomes hypersensitive to testosterone, prostate cancer is the result. The current treatment for prostate cancer, called "hormone therapy", involves lowering the amount of testosterone available (sometimes by castration). Many malignant tumors are resistant to this therapy, however, so we are applying our protein design methodology to find different ways to inhibit the AR and to treat prostate cancer. Specifically, we are trying to design proteins that will disable the AR even in the presence of testosterone. We are doing this by designing proteins that will prevent the AR from entering the nucleus of the cell (which is where it does its dirty work), and also preventing it from binding DNA and activating tumor-specific genes even if it does get into the nucleus.
男性荷尔蒙受体(AR)可以对睾丸激素进行约束,且对男性的生长和发展起着关键作用.一旦AR对睾丸激素变得非常敏感,那么前列腺细胞就有可能癌变.现行的前列腺癌疗法是所谓的”激素疗法”.其目的是降低睾丸激素的效能(有时候可能通过阉割!).这种疗法对很多恶性的肿瘤不起太大的效果.然而我们可以通过设计蛋白质来抑制AR和治疗前列腺癌.很明显,我们的目的就是要使AR对睾丸激素的敏感程度降低,这将可以通过设计新的蛋白质来完成.我们正尝试设计一种可以有效防止AR进入细胞核.即便进入了,我们也可以通过新设计出来的蛋白质来阻止癌变特异基因的启动.
The above projects are not currently running on BOINC because we don't yet have an efficient queuing system which lets people submit jobs easily, but look for them soon! Also, rest assured that the structure prediction calculations currently running on your computers will have direct bearing on treating disease. There is a three-fold explanation for this direct relationship between structure prediction and disease treatment:
我们还没有一个使参与者能有秩序并便捷地申请工作的系统,所以以上的项目都还没能在BOINC上运作.不过这只是暂时的,很快这些项目都会加入BOINC的大家庭中来.当然,现在您电脑上运行所的Rosetta对于防治疾病来说也是具有重大意义的.以下三点对蛋白质结构预测与抵御重大疾病之间的紧密关系做了详细的阐释.
1. Structure prediction and protein design are closely related.
1.蛋白质设计和蛋白质结构预测是紧密相关的.
Improvements in structure prediction lead to improvements in protein design, which in turn can be directly translated into making new enzymes, vaccines, etc. For more information on protein design you might be interested in looking at the review we recently wrote in science which is available at our home page (http://depts.washington.edu/bakerpg).
蛋白质预测技术的进步引领着蛋白质设计技术的前进.蛋白质的设计以蛋白质结构的预测技术作为基础,在此基础上可以设计出新的酶和疫苗等等.更多您可能感兴趣的咨询请参阅我们的主页http://depts.washington.edu/bakerpg,这里面有我们最新得出的科技成就.
Schueler-Furman, O., Wang, C., Bradley, P., Misura, K., Baker, D. (2005). Progress in modeling of protein structures and interactions Science 310, 638-642.
2. Structure prediction identifies targets for new drugs.
2.蛋白质结构预测,研发新药物.
When we predict structures for proteins in the human genome on a large scale, we learn about the functions of many proteins, which will help in understanding how cells work and how disease occurs. More directly, we will be able to identify many new potential drug targets for which small molecule inhibitors (drugs) can be designed. To put this in context, one major road-block to developing new treatments for human disease is identifying new "drugable" protein targets. Most new drugs these days interact with the same targets as the old drugs, so these drugs lead to only small improvements in disease treatment. Structure prediction helps us identify new drug targets, and so will help us find innovative, perhaps even breakthrough, treatments for disease.
当我们在广阔的蛋白质天地中预测人类基因蛋白质结构时,我们对许多其他蛋白质的功能有新的了解.这帮助我们了解细胞的工作原理和疾病时如何发生的.更直接的说,我们将可能找到一些分子抑制剂.联系上下文,您应得知,我们研发对付重大疾病的药物的路上,当务之急就是要找出一些”治疗性的”蛋白质样本.目前,大多数的新药物都是由通过与旧药物一样的蛋白质样本相互作用而成的.预测蛋白质结构有助于我们发现新的更有效的药物.通过蛋白质结构预测和设计技术来医治疾病将会是一种改革,一种突破!
3. Structure prediction allows us to use "rational design" to create new drugs.
3.掌握预测蛋白质结构变化的逻辑规律使我们能创造新药物.
If we know the structure of a protein, we can determine its functional sites, and specifically target those sites to be inactivated by a new drug. Calculation of whether a small molecule (drug) will bind to and inactivate a protein target is similar in many ways to the structure prediction calculations we are doing here--it is basically a problem of finding the lowest energy structure of the protein plus drug system--and we have recently developed a new module in ROSETTA to do this docking problem. Results are very promising, and in the near future your machines will likely be running drug docking calculations along with the vaccine and therapeutic protein design projects described above, in addition to the protein folding calculations you are doing now.
如果我们对一种蛋白质的结构了解透彻了的话,我们可以确定它每一个位点的功能,并能通过新药物来阻止一些不利于我们的功能的正常启用.在许多方面,对新药物的计算和对蛋白质结构预测的计算使基本相同的.不过这只是基础的.计算目的就是要在蛋白质+药物系统中找到能量最低的蛋白质结构.而且最近我们在Rosetta也添加了一个新的模块来完成蛋白质停靠实验.结果使十分令人鼓舞的.在不远的将来,您的Rosetta除了做关于蛋白质结构预测的计算外,还可能帮助我们研发新的药物和疫苗呢! |
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