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Human Plasma Proteome Project

With its central role in human physiology, blood provides a unique window into human health and disease. As it circulates the human body, blood may contain markers indicating changes from homeostasis. Compared to tissue samples, the ease of acquisition and handling makes blood derived specimen an attractive source for building repositories, such as in large scale biobanks. Nevertheless, analyzing blood-derived plasma or serum still poses one of the major challenges for proteomics in terms of sensitivity and analytical depth. With growing numbers of plasma samples being systematically collected, stored, and accessible through biobanks, the HPPP initiative aims to collect the advances in plasma protein analysis from different technologies, diseases, and concepts. This includes bringing together different contributions to the field in mass spectrometry and affinity-based assays and provide a platform to discuss success stories, technological possibilities, viewpoints and perspectives on how plasma proteomics has and will continue to advance.

News:

New draft of the human plasma proteome has been published. In a study lead by Jochen Schwenk and Eric Deutsch, 3,509 proteins have now been reported in plasma and determined by mass spectrometry. The data are accessible through PeptideAtlas. The study also provides a historical view on the HPPP project and discusses the portfolio of targeted MS analysis, available multiplexed affinity assays as well as considerations concerning sample handling and study design.

Current lines of work:

  • Definition of the content of the plasma proteome by characterization in health and disease.
  • To collect protein levels obtained in different studies and with different technologies
  • To develop targeted standardized methods for the quantification of clinically relevant proteins.
  • To identify technologies and advances in plasma analysis
  • To identify requirements in study design, patient and sample related information. 

Overview of Project

The HPPP was initiated in 2002 with a series of planning workshops. During 2003-2005, the HPPP prepared and distributed reference specimens of human serum and EDTA-, citrate-, and heparin-plasma to 55 participating laboratories worldwide. The HPPP stimulated access to emerging technologies and generated substantial datasets and integrated databases for proteins detectable and identifiable in human plasma and serum. Experimental protocols used combinations of depletion, fractionation, mass spectrometry, and immunoassay methods linked via search engines and annotation groups to gene and protein databases. We created a new human plasma proteome database. We concluded that EDTA-plasma is the preferred specimen for studies of plasma or serum from human blood.

A special issue of PROTEOMICS in August 2005 presented 28 articles from the HPPP—both collaborative articles and ancillary analyses stimulated by a special small grants program. Collaborating laboratories and working groups of this Pilot Phase of the HPPP addressed (a) specimen stability and protein concentrations; (b) protein identifications from 18 MS/MS datasets, including subproteome analyses; (c) independent analyses from raw MS/MS spectra; (d) search engine performance; (e) biological annotations and insights; (f) antibody arrays; and (g) direct MS/SELDI analyses. A Core Dataset of proteins identified based on two or more peptides had 3020 protein IDs characterized with Gene Ontology, InterPro, Novartis Atlas, Online Mendelian Inheritance in Man, and immunoassay-based concentration determinations. Using different criteria, several subsets of the Core Dataset were described. The work was also published as a book by Wiley “Exploring the Human Plasma Proteome” in 2006.

In Phase II, the HPPP has grown with the contribution of additional large datasets and standardized analysis using Trans-Proteomic Pipeline to create the current version of the Human Plasma PeptideAtlas. Cross-analyses with the urine, kidney, and liver proteome datasets from the HUPO KHUPP and HLPP initiatives were presented at the Sydney HUPO Congress in 2010 and published by Farrah et al.

In 2017, the HPPP reviewed the history of the projects and the advances made in exploring the human plasma proteome since the inception of the HPPP and reviewed several of its recent achievements. Applying the Human Proteome Project Data Interpretation Guidelines (each with ≥ 2 distinct peptides of ≥ 9 amino acids) to historical PeptideAtlas builds going back to 2006, the HPPP described the progress made in the past ten years in plasma proteome coverage. The latest 2017-04 build of Human Plasma PeptideAtlas contained ∼43 million peptide-spectrum matches and 122,730 distinct peptide sequences from 178 individual experiments, with a 1% protein-level FDR globally across all experiments. This yielded 3509 proteins including > 1300 additional proteins with ambiguous evidence. We further compared this set with proteins of historical PeptideAtlas builds, RNA abundances and cellular localization categories. Our recent work also considered targeted mass spectrometry and multiplexed affinity assays. During early 2017, affinity assays targeted ∼2000 proteins of which half were also described in the 2017-04 built. Lastly, the HPPP brings sample handling and study design into focus during the exploration of the plasma proteome, as these may influence the detectability of existing and novel proteins with the chosen technologies.

Collaborations with other Initiatives:

  • This project is committed to interact with HLPP and HBPP in order to assure analyses of serum and/or plasma side-by-side with analyses of tissue specimens, as forerunner to establishing accessible biomarker assays for tissue proteins of interest in various disease states.
  • Bioinformatics and data analysis and storage issues are done in collaboration with Hermjakob and Apweiler from the Proteomics Standards Initiative.
  • An interaction with the Human Antibody Initiative (HAI) is underway so that any antibodies generated can be added to the HAI database.
  • Plasma proteins accessible to multiple technologies are presents in the HPP Protein List Explorer interface.
  • Bibliometric approach led by Kun-Hsing Yu provides ranked popular protein information for all 22 of our B/D teams.

Key documents related to activities since 2010:

Papers:

  • Schwenk JM, et al., The Human Plasma Proteome Draft of 2017: Building on the Human Plasma PeptideAtlas from Mass Spectrometry and Complementary Assays DOI: 10.1021/acs.jproteome.7b00467
  • Geyer, P. E.; et al. Revisiting biomarker discovery by plasma proteomics. Mol Syst Biol 2017,13 (9), 942.
  • Smith, J. G et al., Emerging Affinity-Based Proteomic Technologies for Large-Scale Plasma Profiling in Cardiovascular Disease. Circulation 2017, 135 (17), 1651−1664.
  • Huang Z, Ma L, Huang C, Li Q, Nice EC., Proteomic profiling of human plasma for cancer biomarker discovery, Proteomics. 2016 Aug 23. doi: 10.1002/pmic.201600240
  • Geyer PE, Kulak NA, Pichler G, Holdt LM, Teupser D, Mann M., Plasma Proteome Profiling to Assess Human Health and Disease, Cell Syst. 2016 Mar 23;2(3):185-95. doi: 10.1016/j.cels.2016.02.015
  • Keshishian H, Burgess MW, Gillette MA, Mertins P, Clauser KR, Mani DR, Kuhn EW, Farrell LA, Gerszten RE, Carr SA, Multiplexed, Quantitative Workflow for Sensitive Biomarker Discovery in Plasma Yields Novel Candidates for Early Myocardial Injury, Mol Cell Proteomics. 2015 Sep;14(9):2375-93. doi: 10.1074/mcp.M114.046813

Related links:

Earlier documents:

  • 2009 Omenn-Aebersold-Paik Proteomics publication about the 2008 Amsterdam Workshop
  • July 2008 Report
  • ProteomExchange data submission strategy final
  • HUPO Plasma Proteome Project Workshop Agenda – October 7, 2007, Seoul
  • September 2007 Report on HUPO Plasma Proteome Project to the initiatives
  • Overview of the HUPO Plasma Proteome Project Results from the pilot phase published in Proteomics Aug 2005 special issue
  • Full list of the 28 publications in Proteomics August 2005
  • U.S. HUPO Meeting plenary presentation March 2005
  • HUPO PPP Update Report
  • HUPO PPP pilot Phase Montreal Workshop Oct 2003
  • HUPO PPP Workshop in Bethesda, July 16-17 2003
  • Data Capture and Data Analysis
  • David States errors and uncertainty in Proteomics
  • Pilot studies with reference specimens
  • HUPO Plasma Proteome Project
  • PPP January 2003 Omenn
  • PPP Questionnaire

Leadership:

Jochen Schwenk (Chair), Sweden

Eric Deutsch (Co-Chair), USA

Vera Ignjatovic, Australia

For more information or participation opportunities please contact office(at)hupo.org.




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