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Biological/Clinical Application 5

PI: Jennifer Van Eyk         Co-PIs: Edward Miller, Josef Coresh, Hui Zhang

Tools and approaches for plasma biomarker development: HF risk stratification

The premise of Project 5 is that identification of specific protein isoforms and/or disease-associated PTMs will increase biomarker specificity. We propose that this added information will refine diagnostic/prognostic measures and allow individualized information for clinical decision making. We will apply these new methods to development of prognostic markers for risk of re-hospitalization in HF – 1.1 million hospitalizations costing $32 billion occurred among the 5 million HF patients in the U.S. in 2006 alone.

As most genes are the same throughout the body, unique aspects of the cell specific proteome arise due to either differences in the protein quantity due to altered gene expression or translation, the selective expression of cell specific isoforms or due to the specific regulation PTMs.  There are currently two major technical limitations to characterize proteins in context of biomarkers which we will address. The first is the lack of tools for de novo discovery of disease-associated PTMs, and the second is a reliable method to quantify specific isoforms and PTMs.

Overall Research Goal:  We will develop and exploit methods targeting specific disease-associated PTMs and isoforms in order to develop biomarkers that allow individualization of clinical decision making for risk stratification of patents with HF.

Goal 1: Targeted discovery of PTMs and isoforms of potential and known HF biomarkers.

Rationale: Over the last three decades, many candidate proteins for HF have been reported. Developing of robust, highly specific and selective ELISA is challenaging due, in part to the requirement of two non-epitope overlapping Abs. MRM over comes this barrier as ELISA are not required.

Goal 2:  PTM-targeted enrichment of candidate proteins in serum and plasma. 

Rationale: We will exploit our newly developed methods for PTM-enrichment to isolate and quantify specificmodified proteins in serum and plasma. It is our expectation that by targeting PTMs we will be able to find commonality between various pathophysiological pathways that reflect the status of HF in each patient.