The promise of biomarker discovery leading to personalized medicine, i.e. improved diagnosis and prognosis, has been widely disseminated and has met with mild success, at best. The most common tool used for biomarker discovery is plasma proteomics because of the accessibility of blood samples and the rapid development of highly sensitive proteomics technologies. The major obstacle for biomarker discovery in plasma samples is the well known dynamic range issue where highly abundant proteins such as serum albumin are 1010 times more abundant than the least concentrated, perhaps most important, marker proteins. The proposed research plan outlines a fundamentally different and novel strategy that combines both transcriptomic and proteomic methodologies that is designed to circumvent the dynamic range issue in plasma proteomics. The specific goal of the proposed research is to develop a combined transcriptomic and proteomics approach to measure disease specific RNA and protein signatures in isolated plasma microvesicles and urinary exosomes. These lipid particles contain both protein and RNA and are known to be secreted at higher rates in cancer and inflammatory diseases;hence, they are currently being investigated as biomarker vectors. The proposed complementary strategy of protein and RNA analysis provides a powerful synergistic approach for elucidating disease- specific signatures with high specificity and sensitivity. To further increase analytical specificity, cell- and tissue-specific microparticles will be isolated from plasma and urine samples to acquire diagnostic markers, mechanistic information, and markers to monitor therapeutic response. Finally, biomarkers will be identified and validated in hypertension, a common human condition, which contributes to the enormous burden of stroke, heart failure, and renal failure unless treated. Hypertensive subjects will be subjected to controlled diet for classification of salt-sensitivity and plasma and urine collection for subsequent molecular analysis and statistical correlation. It is anticipated that a panel of novel biomarkers (both protein and RNA) will be discovered and validated as markers for diagnostic, prognostic, and therapeutic response that will enable improved treatment of hypertension.

Public Health Relevance

The goal of the proposed research is to develop a novel method for discovery of molecular markers of disease that circumvents existing obstacles. Through analysis of proteins and RNA found in lipid particles isolated from blood and urine, new markers of disease will be discovered that improve diagnosis, prognosis, and prediction of response to therapy;that is, improve personalized medicine. The new methodology will be applied to reveal biomarkers of salt- sensitivity and therapeutic response in hypertensive subjects.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
NIH Challenge Grants and Partnerships Program (RC1)
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Special Emphasis Panel (ZRG1-VH-D (58))
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OH, Youngsuk
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Vanderbilt University Medical Center
Schools of Medicine
United States
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Qi, Ying; Wang, Xiaojing; Rose, Kristie L et al. (2016) Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion. J Am Soc Nephrol 27:646-56
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Wang, Zhen; Hill, Salisha; Luther, James M et al. (2012) Proteomic analysis of urine exosomes by multidimensional protein identification technology (MudPIT). Proteomics 12:329-38
Stamer, W D; Hoffman, E A; Luther, J M et al. (2011) Protein profile of exosomes from trabecular meshwork cells. J Proteomics 74:796-804