: 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.
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