This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia characterized by the increased sensitivity of red cells to complement leading to intravascular hemolysis and hemoglobinuria. PNH is due to the expansion of a cell clone that has acquired a mutation in the X-linked PIGA gene. PIGA is an enzyme subunit essential for the synthesis of glycosyl phosphatidylinositol (GPI) anchor molecules. Blood cells derived from the mutant progenitor cell are therefore deficient in all GPI-anchored molecules. The broad long-term objective of our research is to understand the pathophysiology and pathogenesis of PNH. PNH is a chronic disease often associated with substantial morbidity and mortality. Thrombosis is the most frequent cause of death. The pathophysiology of thrombosis in PNH is not understood. We propose that platelets (Plt's) deficient in GPI-linked proteins (PNH phenotype) play a major role in the pathogenesis of thrombosis in PNH. We hypothesize that blood cells with the PNH phenotype not only lack all GPI-linked proteins, but are also deficient in other proteins, whose synthesis or localization is dependent on normal GPI anchor production, and that the deficiencies of these proteins on Plt's might contribute to the prothrombotic risk. In the proposed research we will focus on the molecular aspects of these hypotheses by identifying proteins and protein modification in PNH Plt's that are associated with PNH. First, we will develop reproducible proteomic procedures to isolate and analyze Plt's from normal and PNH patients, and then compare the protein profile from Plts'deficient in GPI-linked proteins with the protein profile of normal Pit's. Finally, we will develop assays to detect and measure candidate proteins or protein modifications specific for PNH cells and verify the differential expression of candidate proteins in a second cohort of patient and control individuals. Our proposed investigations are likely to identify a number of unanticipated proteins, protein interactions, and protein modifications that might significantly advance our understanding of the pathogenesis of thrombosis in PNH and possibly also in other conditions, in which an abnormal clonal hematopoiesis is associated with thrombosis, for example, polycythemia vera or other myeloproliferative syndromes. Established methods for analyzing and comparing the platelet proteome in health and disease might lead to the identification of novel biomarkers useful in evaluating the risk of thrombosis or identify new targets for the development of diagnostics or drugs.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Yue, Xuyi; Dhavale, Dhruva D; Li, Junfeng et al. (2018) Design, synthesis, and in vitro evaluation of quinolinyl analogues for ?-synuclein aggregation. Bioorg Med Chem Lett 28:1011-1019
Ohlemacher, Shannon I; Giblin, Daryl E; d'Avignon, D André et al. (2017) Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria. J Clin Invest 127:4018-4030
Lin, Xiaobo; Racette, Susan B; Ma, Lina et al. (2017) Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans. Arterioscler Thromb Vasc Biol 37:2364-2369
Ovod, Vitaliy; Ramsey, Kara N; Mawuenyega, Kwasi G et al. (2017) Amyloid ? concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13:841-849
Cade, W Todd; Levy, Philip T; Tinius, Rachel A et al. (2017) Markers of maternal and infant metabolism are associated with ventricular dysfunction in infants of obese women with type 2 diabetes. Pediatr Res 82:768-775
Lucey, Brendan P; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2017) Associations Between ?-Amyloid Kinetics and the ?-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol 74:207-215
Wei, Xiaochao; Song, Haowei; Yin, Li et al. (2016) Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature 539:294-298
Shields-Cutler, Robin R; Crowley, Jan R; Miller, Connelly D et al. (2016) Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine. J Biol Chem 291:25901-25910
Mertins, Philipp; Mani, D R; Ruggles, Kelly V et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534:55-62
Murata, Takahiro; Dietrich, Hans H; Horiuchi, Tetsuyoshi et al. (2016) Mechanisms of magnesium-induced vasodilation in cerebral penetrating arterioles. Neurosci Res 107:57-62

Showing the most recent 10 out of 696 publications