NanoSystems Biology Cancer Center

描述（由申请人提供）：由系统生物学研究所开创的生物学和医学的系统方法有望在未来2-15年内改变肿瘤学的实践，将其从反应性学科（在患者生病后做出反应）转变为预测性，预防性和个性化模式。这将在一定程度上通过将血液作为了解健康和疾病的窗口来实现。这种观点认为，生物学是由蛋白质和其他分子网络介导的，这些分子在细胞内运作，通过调节基因表达来执行正常功能。在疾病中，这些网络中的一个或多个受到干扰（遗传或环境），基因表达模式的改变介导疾病。这些受疾病干扰的网络随着疾病的进展而动态变化，就像它们的基因表达模式一样。我们已经通过计算分析确定了前列腺和卵巢中的器官特异性转录本，通过计算分析，其中一些似乎是分泌的。我们的假设是，这些分子中至少有一些以可检测的水平分泌到血液中，因此构成了每个器官的分子指纹，这些器官的蛋白质成分在从正常状态到患病状态以及在疾病状态下的进展过程中，各自的表达水平发生了变化。这些被提出的器官特异性血液标记物的强大之处在于，它们让人们专注于发生在单个器官上的变化，而血液可以清洗所有器官和组织，从而接收来自每个器官和组织的分泌蛋白质指纹。因此，我们计划测试这样一个假设，即这些血液指纹成为一个多参数的蛋白质面板，能够识别特定的疾病和这些疾病的进展状态，并将使用血液蛋白质组学技术来检测三种不同的癌症：前列腺癌、卵巢癌和胶质母细胞瘤。我们还将测试这样一种想法，即这些血液检查可以在早期发现癌症。为了将这些血液诊断技术扩展到数以百万计的病人身上，必须开发出新的测量技术，最终能够进行大约1000次定量蛋白质测量，而且要快速、廉价、在非常小的样本上进行，而且要全自动。因此，在这笔拨款中，我们也将开始使用微流体和纳米技术方法开发血液蛋白测量设备，这些设备将开始获得这些特征。

DESCRIPTION (provided by the applicant): The systems approach to biology and medicine pioneered by the Institute for Systems Biology promises to transform the practice of oncology over the next 2-15 years moving it from a reactive discipline (responding after the patient is sick) to a predictive, preventive and personalize modes. This will be, in part, achieved by using the blood as a window into health and disease. The idea is that biology is mediated by networks of proteins and other molecules that operate within the cell to execute normal functions through the regulation of gene expression. In disease, one or more of these networks becomes perturbed (genetically or environmentally) and the altered patterns of gene expression mediate the disease. These disease-perturbed networks change dynamically with the progression of the diseases, as do their patterns of gene expression. We have identified by computational analyses organ-specific transcripts in the prostate and ovary and again by computational analyses some of these appear to be secreted. Our hypothesis is that at least some of these molecules are secreted into the blood at detectable levels and hence constitute a molecular fingerprint for each organ whose protein components change individually in their levels of expression as one shifts from the normal to a diseased state and as one progresses through the disease state. The power of these proposed organ-specific blood markers is that they let one focus on the changes that occur in just a single organ and that the blood baths all organs and tissues and hence receives secreted protein fingerprints from each. Hence we plan to test the hypothesis that these blood fingerprints become a multiparameter panel of proteins capable of identifying particular diseases and the state of progression of these diseases-and will do using blood proteomics techniques for three different cancers: prostate, ovarian and glioblastoma. We will also test the idea that these blood tests will allow cancer to be detected at a very early stage. The need to extend these blood diagnostic techniques in the future to millions of patients means that new measuring techniques will have to be developed which are ultimately capable of making perhaps 1000 quantitative protein measurements-and doing so rapidly, cheaply, on very small samples and fully automatically. Hence in this grant we will also begin to develop blood-protein measuring devices using microfluidic and nanotechnology approaches that will begin to acquire these features.