Body fluid proteomics: Prospects for biomarker discovery

Many diseases are caused by perturbations of cellular signaling pathways and related pathway Received: March 2, 2007 networks as a result of genetic aberrations. These perturbations are manifested by altered cellular Revised: April 19, 2007 protein profiles in the fluids bathing tissue/organs (i.e., the tissue interstitial fluid, TIF). A major Accepted: April 23, 2007 challenge of clinical chemistry is to quantitatively map these perturbed protein profiles - the socalled signatures of disease - using modem proteomic technologies. This information can be utilized to design protein biomarkers for the early detection of disease, monitoring disease progression and efficacy of drug action. Here, we discuss the use of body fluids in the context of prospective biomarker discovery, and the marked 1000-1500-fold dilution of body fluid proteins, during their passage from TIF to the circulatory system. Further, we discuss proteomics strategies aimed at depleting major serum proteins, especially albumin, in order to focus on low-abundance protein/peptides in plasma. A major limitation of depletion strategies is the removal of low-molecular weight protein/peptides which specifically bind major plasma proteins. We present a prototype model, using albumin, for understanding the multifaceted nature of biomarker research, highlighting the involvement of albumin in Alzheimer's disease. This model underscores the need for a system-level understanding for biomarker research and personalized medicine.